Enantioselective cross dehydrogenative coupling reactions and compounds synthesized by the reactions

ABSTRACT

Disclosed are enantioselective cross dehydrogenative coupling reactions for synthesizing tetrahydropyran compounds. Novel tetrahydropyran compounds may be synthesized by the disclosed methods as well as tetrahydropyran precursor compounds for synthesizing various naturally occurring compounds. The enantioselective cross dehydrogenative coupling reactions utilize in situ Lewis Acid activation in combination with oxidative formation of an oxocarbenium ion to provide a highly efficient and selective coupling reaction for synthesizing tetrahydropyran compounds.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/710,512, filed on Dec. 11, 2019, now U.S. Pat. No.11,174,238, and claims the benefit of priority under 35 U.S.C. § 119(e)to U.S. Provisional Patent Application No. 62/778,016, filed on Dec. 11,2018, of which the content of each is incorporated herein by referencein their entireties.

BACKGROUND

The field of the invention relates to tetrahydropyran compounds andmethods for synthesizing tetrahydropyran compounds. In particular, thefield of the invention relates to enantioselective cross dehydrogenativecoupling reactions for synthesizing tetrahydropyran compounds

Tetrahydropyrans (THPs) are key structural elements in numerousbioactive natural products and medicinally relevant compounds.¹ Due tothe prevalence of THPs, multiple stereoselective processes have beendeveloped for their construction, including Prins cyclizations,²hetero-Diels-Alder reactions,³ and intramolecular nucleophilic conjugateadditions.⁴ Established methods to construct THPs in an enantioselectivefashion typically focus on conjugate additions⁵ or activation byenamine/iminium intermediates,⁶ two approaches that are deployedextensively in total synthesis. Inspired by natural product targets ofinterest in our laboratory, as well as small molecules possessingintriguing biological activity, we envisioned a complementary and directmethod for the enantioselective synthesis of substitutedtetrahydropyran-4-ones. The inventors have disclosed the use ofβ-hydroxy dioxinones as nucleophiles with aldehydes and isatins toundergo mild and stereoselective cyclizations in the presence ofcatalytic Lewis or Brønsted acids to access enantioenriched THPs.⁷ Theinventors' efforts in this area have enabled total syntheses of variousnatural products including exiguolide,⁸ neopeltolide,⁹ okilactomycin,¹⁰and other naturally occurring compounds containing THPs.¹¹ Conceptually,moving beyond preformed nucleophiles such as dioxinones to simpleβ-ketoester systems presents opportunities for enantiocontrol, mostlikely through two-point/chelate binding, but also requires differentactivation modes to operate simultaneously in a single reaction flask.

Here, the inventors disclose an enantioselective cross-dehydrogenativecoupling (CDC) reaction which may be utilized to preparetetrahydropyrans and derivatives thereof. The disclosed CDC reactioncombines in situ Lewis acid activation of a nucleophile together withthe oxidative formation of a transient oxocarbenium electrophile, whichleads to a productive and highly enantioselective CDC reaction. Thedisclosed CDC reaction represents one of the first successfulapplications of CDC for the enantioselective couplings ofunfunctionalized ethers. The disclosed CDC reactions may be utilized toaccess valuable tetrahydropyran motifs found in many natural productsand bioactive small molecules.

SUMMARY

Disclosed are enantioselective cross dehydrogenative coupling reactionsfor synthesizing tetrahydropyran compounds. Novel tetrahydropyrancompounds may be synthesized by the disclosed methods as well astetrahydropyran precursor compounds for synthesizing various naturallyoccurring compounds. The enantioselective cross dehydrogenative couplingreactions utilize in situ Lewis Acid activation in combination withoxidative formation of an oxocarbenium ion to provide a highly efficientand selective coupling reaction for synthesizing tetrahydropyrancompounds.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Stereochemical induction model with1a/(2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) intermediate.

FIG. 2. ORTEP representation (50% probability) of the crystal structureof 2h.

FIG. 3. PM3 optimized structure of L3.Cu(II) with1a/(2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) intermediate.

FIG. 4. PM3 optimized structure of L3.Cu(II)(H₂O)₂.

FIG. 5. CDC Processes and Reaction Design.

DETAILED DESCRIPTION

The disclosed subject matter further may be described utilizing terms asdefined below.

Unless otherwise specified or indicated by context, the terms “a”, “an”,and “the” mean “one or more.” For example, “a compound” should beinterpreted to mean “one or more compounds.”

As used herein, “about”, “approximately,” “substantially,” and“significantly” will be understood by persons of ordinary skill in theart and will vary to some extent on the context in which they are used.If there are uses of the term which are not clear to persons of ordinaryskill in the art given the context in which it is used, “about” and“approximately” will mean plus or minus ≤10% of the particular term and“substantially” and “significantly” will mean plus or minus >10% of theparticular term.

As used herein, the terms “include” and “including” have the samemeaning as the terms “comprise” and “comprising.” The terms “comprise”and “comprising” should be interpreted as being “open” transitionalterms that permit the inclusion of additional components further tothose components recited in the claims. The terms “consist” and“consisting of” should be interpreted as being “closed” transitionalterms that do not permit the inclusion additional components other thanthe components recited in the claims. The term “consisting essentiallyof” should be interpreted to be partially closed and allowing theinclusion only of additional components that do not fundamentally alterthe nature of the claimed subject matter.

New Chemical Entities and Methods of Synthesis

New chemical entities and uses for chemical entities are disclosedherein. The chemical entities may be described using terminology knownin the art and further discussed below.

As used herein, an asterisk “*” or a plus sign “+” may be used todesignate the point of attachment for any radical group or substituentgroup.

The term “alkyl” as contemplated herein includes a straight-chain orbranched alkyl radical in all of its isomeric forms, such as a straightor branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to hereinas C1-C12 alkyl, C1-C10-alkyl, and C1-C6-alkyl, respectively.

The term “alkylene” refers to a diradical of an alkyl group (e.g.,—(CH₂)_(n)— where n is an integer such as an integer between 1 and 20).An exemplary alkylene group is —CH₂CH₂—.

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. For example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃,and the like.

The term “heteroalkyl” as used herein refers to an “alkyl” group inwhich at least one carbon atom has been replaced with a heteroatom(e.g., an O, N, or S atom). One type of heteroalkyl group is an “alkoxy”group.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C2-C12-alkenyl, C2-C10-alkenyl, and C2-C6-alkenyl,respectively.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C2-C12-alkynyl, C2-C10-alkynyl, and C2-C6-alkynyl,respectively.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8,or 4-6 carbons, referred to herein, e.g., as “C4-8-cycloalkyl,” derivedfrom a cycloalkane. Unless specified otherwise, cycloalkyl groups areoptionally substituted at one or more ring positions with, for example,alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino,amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halo, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato,phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Incertain embodiments, the cycloalkyl group is not substituted, i.e., itis unsubstituted.

The term “cycloalkylene” refers to a cycloalkyl group that isunsaturated at one or more ring bonds.

The term “partially unsaturated carbocyclyl” refers to a monovalentcyclic hydrocarbon that contains at least one double bond between ringatoms where at least one ring of the carbocyclyl is not aromatic. Thepartially unsaturated carbocyclyl may be characterized according to thenumber of ring carbon atoms. For example, the partially unsaturatedcarbocyclyl may contain 5-14, 5-12, 5-8, or 5-6 ring carbon atoms, andaccordingly be referred to as a 5-14, 5-12, 5-8, or 5-6 memberedpartially unsaturated carbocyclyl, respectively. The partiallyunsaturated carbocyclyl may be in the form of a monocyclic carbocycle,bicyclic carbocycle, tricyclic carbocycle, bridged carbocycle,spirocyclic carbocycle, or other carbocyclic ring system. Exemplarypartially unsaturated carbocyclyl groups include cycloalkenyl groups andbicyclic carbocyclyl groups that are partially unsaturated. Unlessspecified otherwise, partially unsaturated carbocyclyl groups areoptionally substituted at one or more ring positions with, for example,alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino,amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato,phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Incertain embodiments, the partially unsaturated carbocyclyl is notsubstituted, i.e., it is unsubstituted.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. The term “aryl” includes polycyclic ring systems havingtwo or more carbocyclic rings in which two or more carbons are common totwo adjoining rings (the rings are “fused rings”) wherein at least oneof the rings is aromatic and, e.g., the other ring(s) may becycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Unlessspecified otherwise, the aromatic ring may be substituted at one or morering positions with, for example, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl,carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide,ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties,—CF₃, —CN, or the like. In certain embodiments, the aromatic ring issubstituted at one or more ring positions with halogen, alkyl, hydroxyl,or alkoxyl. In certain other embodiments, the aromatic ring is notsubstituted, i.e., it is unsubstituted. In certain embodiments, the arylgroup is a 6-10 membered ring structure.

The terms “heterocyclyl” and “heterocyclic group” are art-recognized andrefer to saturated, partially unsaturated, or aromatic 3- to 10-memberedring structures, alternatively 3- to 7-membered rings, whose ringstructures include one to four heteroatoms, such as nitrogen, oxygen,and sulfur. The number of ring atoms in the heterocyclyl group can bespecified using 5 Cx-Cx nomenclature where x is an integer specifyingthe number of ring atoms. For example, a C3-C7 heterocyclyl group refersto a saturated or partially unsaturated 3- to 7-membered ring structurecontaining one to four heteroatoms, such as nitrogen, oxygen, andsulfur. The designation “C3-C7” indicates that the heterocyclic ringcontains a total of from 3 to 7 ring atoms, inclusive of any heteroatomsthat occupy a ring atom position.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines (e.g., mono-substituted amines ordi-substituted amines), wherein substituents may include, for example,alkyl, cycloalkyl, heterocyclyl, alkenyl, and aryl.

The terms “alkoxy” or “alkoxyl” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxy groups include methoxy, ethoxy, tert-butoxy andthe like.

An “ether” is two hydrocarbons covalently linked by an oxygen.Accordingly, the substituent of an alkyl that renders that alkyl anether is or resembles an alkoxyl, such as may be represented by one of—O-alkyl, —O-alkenyl, —O-alkynyl, and the like.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “oxo” refers to a divalent oxygen atom —O—.

The term “carboxamido” as used herein refers to the radical —C(O)NRR′,where R and R′ may be the same or different. R and R′, for example, maybe independently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl,heteroaryl, or heterocyclyl.

The term “carboxy” as used herein refers to the radical —COOH or itscorresponding salts, e.g. —COONa, etc.

The term “amide” or “amido” or “amidyl” as used herein refers to aradical of the form —R¹C(O)N(R²)—, —R¹C(O)N(R²)R³—, —C(O)NR²R³, or—C(O)NH₂, wherein R¹, R² and R³, for example, are each independentlyalkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl,heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” or “+” or “−” depending on the configuration ofsubstituents around the stereogenic carbon atom and or the opticalrotation observed. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers includeenantiomers and diastereomers. Mixtures of enantiomers or diastereomersmay be designated (±)” in nomenclature, but the skilled artisan willrecognize that a structure may denote a chiral center implicitly. It isunderstood that graphical depictions of chemical structures, e.g.,generic chemical structures, encompass all stereoisomeric forms of thespecified compounds, unless indicated otherwise. Also contemplatedherein are compositions comprising, consisting essentially of, orconsisting of an enantiopure compound, which composition may comprise,consist essential of, or consist of at least about 50%, 60%, 70%, 80%,90%, 95%, 96%, 97%, 98%, 99%, or 100% of a single enantiomer of a givencompound (e.g., at least about 99% of an R enantiomer of a givencompound).

Enantioselective Cross Dehydrogenative Coupling Reactions and CompoundsSynthesized the Reactions

The subject matter of the application relates to enantioselective crossdehydrogenative coupling reactions for synthesizing tetrahydropyrancompounds. Novel tetrahydropyran compounds may be synthesized by thedisclosed methods as well as tetrahydropyran precursor compounds forsynthesizing various natural occurring compounds.

In some embodiments, the disclosed compounds may have Formula I or atautomer thereof:

where:X is hydrogen or alkyl (e.g. methyl);n is 0-6;R¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or aryl, optionallywherein R¹ is a single 5-membered or 6-membered ring or two or morefused 5-membered or 6-membered rings, wherein the single ring or two ormore fused rings are carbocyclic or heterocyclic rings containing one ormore heteroatoms selected from N, O, and S, and wherein the ring or twoor more fused rings are saturated or unsaturated at one or more bonds,optionally wherein the single ring or more fused rings are substitutedat one or more positions with a substituent selected from alkyl, alkoxy,halo, amino, and cyano;R² is hydrogen, alkyl, aryl,

wherein R⁸ is hydrogen, alkyl, or aryl;R³ is hydrogen, hydroxyl, or oxo;R⁴ is hydrogen or alkyl; andR⁵ is hydrogen or

R⁶ is hydrogen, hydroxyl, or oxo; andR⁷ is hydrogen or alkyl.

In some embodiments of the disclosed compounds, n is 0-2 and R¹ isselected from phenyl (optionally substituted at one or more positionswith alkyl, alkoxy (e.g., 4-methoxy, 3,4-dimethoxy, or3,4,5-trimethoxy), halo, or haloalkyl (e.g., trifluoromethyl)), naphthyl(e.g., naphth-1-yl or naphtha-2-yl), indolyl (e.g., indol-3-yl),thiazolyl (e.g., thiazol-2-yl).

In some embodiments, disclosed compounds may have a formula selectedfrom:

In some embodiments, the disclosed compounds may have a formula selectedfrom:

In some embodiments, the disclosed compounds may be utilized, forexample as precursors, to prepare naturally occurring or man-madeproducts. Naturally occurring products that may be prepared using thedisclosed compounds include, but are not limited to exiguolide,neopeltolide, and okilactomycin and other compounds that containtetrahydropyrans. (See, e.g., Crane, E. A.; Zabawa, T. P.; Farmer, R.L.; Scheidt, K. A. Angew. Chem. Int. Ed. 2011, 50, 9112-9115; Custar, D.W.; Zabawa, T. P.; Hines, J.; Crews, C. M.; Scheidt, K. A. J. Am. Chem.Soc. 2009, 131, 12406-12414; Custar, D. W.; Zabawa, T. P.; Scheidt, K.A. J. Am. Chem. Soc. 2008, 130, 804-805; Tenenbaum, J. M.; Morris, W.J.; Custar, D. W.; Scheidt, K. A. Angew. Chem. Int. Ed. 2011, 50,5892-5895; Lee, K.; Kim, H.; Hong, J. Org. Lett. 2011, 13, 2722-2725;Lee, K.; Kim, H.; Hong, J. Angew. Chem. Int. Ed. 2012, 51, 5735-5738;Han, X.; Peh, G.; Floreancig, P. E. Eur. J. Org. Chem. 2013, 2013,1193-1208; and Nasir, N. M.; Ermanis, K.; Clarke, P. A. Org. Biomol.Chem. 2014, 12, 3323-3335; the contents of which are incorporated hereinby reference in their entireties.

In some embodiments, the disclosed compounds or pharmaceutical salts orhydrates thereof may be formulated as pharmaceutical composition. Forexample, the disclosed compounds or pharmaceutical salts or hydratesthereof may be formulated together with a pharmaceutical carrier toprepare a pharmaceutical composition.

Also disclosed herein are novel complexes. In some embodiments, thedisclosed complexes have a formula represented as L.M²⁺(OTf)₂, wherein Mis a divalent metal such as Cu(II), Tf is triflyl, and L has a formula:

where R⁹ and R^(9′) together form a 3-membered, 4-membered, 5-membered,or 6-membered carbocyclic ring; andR¹⁰ and R¹¹ are alkyl (e.g., n-butyl).

In some embodiments of the disclosed complexes, L may have a formulaselected from:

The compounds disclosed herein may be prepared by methods that include,but are not limited to a method comprising reacting a mixturecomprising:

-   (a) a compound having a formula

-   -   wherein:    -   X is hydrogen or alkyl (e.g. methyl);    -   n is 0-6;    -   R¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or aryl,        optionally wherein R¹ is a single 5-membered or 6-membered ring        or two or more fused 5-membered or 6-membered rings, wherein the        single ring or two or more fused rings are carbocyclic or        heterocyclic rings containing one or more heteroatoms selected        from N, O, and S, and wherein the ring or two or more fused        rings are saturated or unsaturated at one or more bonds,        optionally wherein the single ring or more fused rings are        substituted at one or more positions with a substituent selected        from alkyl, alkoxy, halo, amino, and cyano; and    -   R⁷ is hydrogen or alkyl;

-   (b) a complex having a formula L.M²⁺(OTf)₂, wherein M is a divalent    metal (e.g., such as Cu(II)), Tf is triflyl, and L has a formula:

-   -   wherein R⁹ and R¹⁰ are independently selected from alkyl,        phenyl, or R⁹ and R¹⁰ together form a 3-membered, 4-membered,        5-membered, or 6-membered carbocylic ring; and    -   R¹⁰ and R¹¹ are alkyl (e.g., n-butyl);    -   optionally wherein L has a formula selected from:

-   (c) an oxidant (optionally wherein the oxidant is    (2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)); and

optionally

-   (d) a salt (optionally wherein the salt is a sodium salt such as a    sodium phosphate salt such as disodium phosphate).

In some embodiments of the disclosed reactions, the reaction mixture maybe prepared using a solvent. Suitable solvents may include but are notlimited to halogenated alkanes such as dichloromethane.

In some embodiments of the disclosed reactions, the reaction may beperformed at a relatively low temperature. Suitable temperatures forperforming the disclosed reactions may include temperatures of less thanabout 0, ⁻10, ⁻20, ⁻30, ⁻40, ⁻50, ⁻60, ⁻70, ⁻80, ⁻90, or ⁻100° C. or atemperature range bounded by any of these values (e.g., ⁻50-⁻90° C.).

In some embodiments of the disclosed reactions, the reaction may beperformed utilizing a molecular sieve (MS). In some embodiments, the MShas an average effective pore diameter of less than about 20, 10, 8, 6,4, or 2 angstroms (Å) or a diameter range bounded by any of these values(e.g., 2-6 Å).

As noted, the compounds disclosed herein may have several chiralcenters, and stereoisomers, epimers, and enantiomers are contemplated.The compounds may be optically pure with respect to one or more chiralcenters (e.g., some or all of the chiral centers may be completely inthe S configuration; some or all of the chiral centers may be completelyin the R configuration; etc.). Additionally or alternatively, one ormore of the chiral centers may be present as a mixture of configurations(e.g., a racemic or another mixture of the R configuration and the Sconfiguration). Compositions comprising substantially purifiedstereoisomers, epimers, or enantiomers, or analogs or derivativesthereof are contemplated herein (e.g., a composition comprising at leastabout 90%, 95%, 99% or 100% pure stereoisomer, epimer, or enantiomer.)As used herein, formulae which do not specify the orientation at one ormore chiral centers are meant to encompass all orientations and mixturesthereof.

ILLUSTRATIVE EMBODIMENTS

The following embodiments are illustrative and should not be interpretedto limit the scope of the claimed subject matter.

Embodiment 1. A compound having Formula I or a tautomer thereof:

wherein:

-   X is hydrogen or alkyl (e.g. methyl);-   n is 0-6;-   R¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or aryl,    optionally wherein R¹ is a single 5-membered or 6-membered ring or    two or more fused 5-membered or 6-membered rings, wherein the single    ring or two or more fused rings are carbocyclic or heterocyclic    rings containing one or more heteroatoms selected from N, O, and S,    and wherein the ring or two or more fused rings are saturated or    unsaturated at one or more bonds, optionally wherein the single ring    or more fused rings are substituted at one or more positions with a    substituent selected from alkyl, alkoxy, halo, amino, and cyano;-   R² is hydrogen, alkyl, aryl,

wherein R⁸ is hydrogen, alkyl, or aryl;

-   R³ is hydrogen, hydroxyl, or oxo;-   R⁴ is hydrogen or alkyl;-   R⁵ is hydrogen or

-   R⁶ is hydrogen, hydroxyl, or oxo; and-   R⁷ is hydrogen or alkyl.

Embodiment 2. The compound of embodiment 1 having a Formula I(a) or atautomer thereof:

Embodiment 3. The compound of embodiment 1 having a Formula I(b) or atautomer thereof:

Embodiment 4. The compound of embodiment 1 having a Formula Ic or atautomer thereof:

Embodiment 5. The compound of embodiment 1 having a Formula Id or atautomer thereof:

Embodiment 6. The compound of embodiment 1 having a Formula I(e) or atautomer thereof:

Embodiment 7. The compound of embodiment 1, wherein n is 0-2 and R¹ isselected from phenyl (optionally substituted at one or more positionswith alkyl, alkoxy (e.g., 4-methoxy, 3,4-dimethoxy, or3,4,5-trimethoxy), halo, or haloalkyl (e.g., trifluoromethyl)), naphthyl(e.g., naphth-1-yl or naphtha-2-yl), indolyl (e.g., indol-3-yl),thiazolyl (e.g., thiazol-2-yl).

Embodiment 8. The compound of embodiment 1 having a Formula I(f):

Embodiment 9. The compound of embodiment 1 having a Formula I(g):

Embodiment 10. The compound of embodiment 1 having a Formula I(h) or atautomer thereof:

Embodiment 11. The compound of embodiment 1 having a Formula I(i) or atautomer thereof:

Embodiment 12. The compound of embodiment 1 having a Formula I(j):

Embodiment 13. The compound of embodiment 1 having a Formula I(k) or atautomer thereof:

Embodiment 14. The compound of embodiment 1 having a Formula I(l) or atautomer thereof:

Embodiment 15. The compound of any of the foregoing embodiments having aformula selected from:

Embodiment 16. A pharmaceutical composition comprising any of thecompounds of the foregoing embodiments or a pharmaceutical salt orhydrate thereof together with a pharmaceutical carrier.

Embodiment 17. A complex having a formula represented as L.M²⁺(OTf)₂,wherein M is a divalent metal (e.g., Cu(II)), Tf is triflyl, and L has aformula:

Wherein:

-   R⁹ and R^(9′) together form a 3-membered, 4-membered, 5-membered, or    6-membered carbocyclic ring; and-   R¹⁰ and R¹¹ are alkyl (e.g., n-butyl).

Embodiment 18. The complex of embodiment 17, wherein L has a formula:

Embodiment 19. The complex of embodiment 17, wherein L has a formula:

Embodiment 20. The complex of embodiment 17, wherein L has a formula:

Embodiment 21. The complex of embodiment 17, wherein L has a formula:

Embodiment 22. A method for preparing any of the compounds ofembodiments 1-15, the method comprising reacting a mixture comprising:

-   -   (a) a compound having a formula

-   -   -   wherein:        -   X is hydrogen or alkyl (e.g. methyl)        -   n is 0-6;        -   R¹ is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, or            aryl, optionally wherein R¹ is a single 5-membered or            6-membered ring or two or more fused 5-membered or            6-membered rings, wherein the single ring or two or more            fused rings are carbocyclic or heterocyclic rings containing            one or more heteroatoms selected from N, O, and S, and            wherein the ring or two or more fused rings are saturated or            unsaturated at one or more bonds, optionally wherein the            single ring or more fused rings are substituted at one or            more positions with a substituent selected from alkyl,            alkoxy, halo, amino, and cyano; and        -   R⁷ is hydrogen or alkyl;

    -   (b) a complex having a formula L.M²⁺(OTf)₂, wherein M is a        divalent metal, Tf is triflyl, and L has a formula:

-   -   -   wherein:        -   R⁹ and R^(9′) are independently selected from alkyl, phenyl,            or R⁹ and R^(9′) together form a 3-membered, 4-membered,            5-membered, or 6-membered carbocylic ring; and        -   R¹⁰ and R¹¹ are alkyl (e.g., n-butyl);        -   optionally wherein the complex is the complex of any of            embodiments 16-20;

    -   (c) an oxidant (optionally wherein the oxidant is        (2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)); and optionally

    -   (d) a salt (optionally wherein the salt is a sodium salt such as        a sodium phosphate salt such as disodium phosphate).

EXAMPLES

The followings Examples are illustrative only and should not beinterpreted to limit the scope of the claimed subject matter.

Example 1

Title—Enantioselective Cross Dehydrogenative Coupling Reactions

Technical Field

The technical field of the disclosed subject matter relates toenantioselective cross dehydrogenative coupling (CDC) reactions and theuse of the enantioselective CDC reactions for preparing compounds suchas tetrahydropyrans and derivatives thereof.

Abstract

The inventors have developed an enantioselective cross-dehydrogenativecoupling (CDC) reaction which may be utilized to preparetetrahydropyrans and derivatives thereof. The disclosed CDC reactioncombines in situ Lewis acid activation of a nucleophile together withthe oxidative formation of a transient oxocarbenium electrophile, whichleads to a productive and highly enantioselective CDC reaction. Thedisclosed CDC reaction represents one of the first successfulapplications of CDC for the enantioselective couplings ofunfunctionalized ethers. The disclosed CDC reactions may be utilized toaccess valuable tetrahydropyran motifs found in many natural productsand bioactive small molecules.

Applications

The applications of the disclosed technology include, but are notlimited to: (i) access to tetrahydropyran motifs found in many naturalproduct and bioactive small molecules; and (ii) expansion of synthetictechnology into different catalytic manifolds, for example, by usingsimilar chemical set-ups as disclosed herein of different chemicalstructural classes to provided different product scaffolds.

Advantages

The advantages of the disclosed technology include, but are not limitedto: (i) the disclosed technology allows for the use of unfunctionalizedstarting materials to access the core structural motif focused on inthis work (i.e. pyrans); (ii) the disclosed technology is easy toimplement into a standard chemical workflow (i.e., no specializedequipment is necessary for others to practice the disclosed technology);and (iii) the disclosed technology can be used to prepare diversechemical products in ways that have not been previously reported orextensively explored.

Brief Summary of the Technology

The technology relates to enantioselective cross-dehydrogenativecoupling (CDC) reactions that utilize in situ Lewis Acid activation incombination with oxidative formation of an oxocarbenium ion to provide ahighly efficient and selective coupling reaction. The technology furtheris disclosed in Example 2 below and in Lee et al., “An EnantioselectiveCross-Dehydrogenative Coupling Catalysis Approach to SubstitutedTetrahydropyrans,” J. Am. Chem. Soc. 2018, 140, 6212-6216; the contentof which is incorporated herein by reference in its entirety.

Technical Description

Using catalytic amounts of a chiral Cu(II)-Box complex in combinationwith an organic oxidant (2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)),which was added dropwise via a syringe pump, we have demonstrated theenantioselective construction of pyranones from unfunctionalized ethers.The disclosed reaction is straightforward and simple to setup, where allof the necessary equipment should be found in a standard organicchemistry laboratory.

Others have tried using other catalyst manifolds to afford constructionof similar chemical compounds. However, previous attempts have sufferedfrom a lack of efficiency and only a small collection of chemicalcompounds that are compatible with the catalyst manifold.

Prior to the disclosure of this work, there were no concise andefficient methods to access pyrans from unfunctionalized startingmaterials. Pyrans are a common structural motif found in medicinallyrelevant natural products. With the disclosure of this work, theinventors have provided state-of-the-art technology to access thesecompounds.

Example 2

Reference is made to Lee et al., “An EnantioselectiveCross-Dehydrogenative Coupling Catalysis Approach to SubstitutedTetrahydropyrans,” J. Am. Chem. Soc. 2018, 140, 6212-6216, the contentof which is incorporated herein by reference in its entirety.

Title—An Enantioselective Cross-Dehydrogenative Coupling CatalysisApproach to Substituted Tetrahydropyrans

Abstract

An enantioselective cross-dehydrogenative coupling (CDC) reaction toaccess tetrahydropyrans has been developed. This process combines insitu Lewis acid activation of a nucleophile in concert with theoxidative formation of a transient oxocarbenium electrophile, leading toa productive and highly enantioselective CDC. These advances representone of the first successful applications of CDC for the enantioselectivecouplings of unfunctionalized ethers. This system provides efficientaccess to valuable THP motifs found in many natural products andbioactive small molecules.

Introduction

Tetrahydropyrans (THPs) are key structural elements in numerousbioactive natural products and medicinally relevant compounds.¹ Due tothe prevalence of THPs, multiple stereoselective processes have beendeveloped for their construction, including Prins cyclizations,²hetero-Diels-Alder reactions,³ and intramolecular nucleophilic conjugateadditions.⁴ Established methods to construct THPs in an enantioselectivefashion typically focus on conjugate additions⁵ or activation byenamine/iminium intermediates,⁶ two approaches that are deployedextensively in total synthesis. Inspired by natural product targets ofinterest in our laboratory, as well as small molecules possessingintriguing biological activity, we envisioned a complementary and directmethod for the enantioselective synthesis of substitutedtetrahydropyran-4-ones. We have disclosed the use of β-hydroxydioxinones as nucleophiles with aldehydes and isatins to undergo mildand stereoselective cyclizations in the presence of catalytic Lewis orBrønsted acids to access enantioenriched THPs.⁷ Our efforts in this areahave enabled total syntheses of various natural products includingexiguolide,⁸ neopeltolide,⁹ okilactomycin,¹⁰ and other naturallyoccurring compounds containing THPs.¹¹ Conceptually, moving beyondpreformed nucleophiles such as dioxinones to simple β-ketoester systemspresents opportunities for enantiocontrol, most likely throughtwo-point/chelate binding, but also requires different activation modesto operate simultaneously in a single reaction flask.

Cross-dehydrogenative coupling (CDC) reactions have emerged as powerfulapproaches to forge C—C bonds from inert C—H bonds.¹² As a subset of C—Hfunctionalization processes,¹³ CDC reactions are attractive because theydo not require prefunctionalized starting materials, relying instead onoxidative activation followed by net loss of H₂ to facilitate C—C bondformation. Specifically, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)a strong oxidizing agent, promotes the formation of stabilizedcarbocations by benzylic and allylic C—H bond activation, and subsequentC—C bond formation.¹⁴ Mechanistically, DDQ mediated CDC reactionsproceed via single electron transfer to form stabilized radical cations,followed by hydrogen atom abstraction to form the electrophilic couplingpartner (e.g., oxocarbenium ion, iminium ion). Floreancig haseffectively demonstrated that DDQ activation can facilitate racemicaccess to carbocycles and heterocycles via the oxidation of allylicethers.¹⁵ Although enantioselective CDC reactions have been reportedduring the last decade,¹⁶ there is a dearth of highly enantioselectiveCDC reactions using oxocarbenium ion electrophiles in contrast to aplethora of enantioselective CDC reactions using iminium electrophiles(Scheme 1b).¹⁷ A major challenge to this approach is successfullyintegrating strongly oxidative conditions for oxocarbenium ion formation(e.g., DDQ) with stereodefining catalysts necessary for nucleophileactivation (e.g., chiral Lewis acids) to a) promote a productivereaction, and b) induce stereocontrol around a transient, highlyreactive oxocarbenium ion. Here, we report an enantioselective CDC ofβ-ketoesters with oxocarbenium ions to access substitutedtetrahydropyrans with high yields and enantioselectivity through amerged chiral Lewis acid/oxidation strategy (Scheme 1c).

Scheme 1. CDC Processes and Reaction Design

(See FIG. 5)

Results and Discussion

We initiated our investigations of this chiral Lewis acid/oxidantprocess using β-ketoester substrate 1a and found thatCu(II)-bisoxazoline (BOX) complex L1.Cu(OTf)₂ gave the desired product2a as the sole diastereomer in 72% yield and 92:8 er at −70° C. (Scheme2). Additional screening with chiral BOX ligands L2-L5 identified ligandL3 as optimal, furnishing 2a in 83% yield and 95:5 er upon furtherreaction dilution to 0.02 M.

After optimization the basic asymmetric CDC reaction with β-ketoester1a, the general scope was explored (Table 1). When the aromatic ring onthe cinnamyl ether was substituted with electron-donating groups at itspara, meta, or ortho position, the reactions provided desirabletetrahydropyran-4-ones 2c-2g in high yields and stereoselectivity withexception of 2b. We observed that substrate 1b possessing ap-methoxycinnamyl group produced side products due to over-oxidation.Furthermore, reaction of 1b without a Cu(II) catalyst produced rac-2b in70% yield in only 1 hour, suggesting the competitive background reactionof this highly reactive substrate also contributed to the observedreduction in stereoselectivity.

TABLE 1 Substrate Scope of β-Keto Esters 1^(a)

^(a)See Materials and Methods below for reaction details. Er determinedby chiral-phase SFC analysis. Products 2 were obtained with >20:1 dr(trans/cis). ^(b)Performed at −30° C.

We then evaluated substrates substituted with electron-withdrawinggroups at para, meta, and ortho positions. The reactions of 1h-1kprovided desired products 2h-2 k in moderate yields and highstereoselectivity. The results showed that high yields andstereoselectivity were observed for 1l and 1m containing naphthylgroups. The reaction of 1n containing a trisubstituted cinnamyl alkeneafforded 2n in 87% yield and 97:3 er, while heteroaryl and conjugatedethers 1o-1q gave tetrahydropyran-4-ones 2o-2 q in somewhat decreasedyields and stereoselectivities. A survey of benzyl ethers revealed thatonly 4-methoxy-substituted substrates 1r-1t were capable of producingdesired products 2r-2t with high stereoselectivity and moderate yield.Under the current conditions, we have not observed productive reactionsusing propargylic, unsubstituted allylic or ether substrates leading totetrahydrofurans (i.e., 5 atom tether length). Instead, over-oxidationor no oxidation is observed (see Supp. Info.). However, with thissuccessful proof of concept, investigations with various oxidationmethods and Lewis acids to engage an even larger range of substrateclasses are ongoing.

Attempts to access enantioenriched tetrahydropyran-4-ones without theβ-ketoester were unsuccessful, as enol acetate 3 provided racemic 4 in68% yield (Scheme 3a). This observation supports the hypothesis that theβ-ketoester is crucial for stereoselectivity by coordination with theCu(II)/BOX catalyst. In an attempt to probe whether an enantioselectiveintermolecular CDC reaction was possible, cinnamyl methyl ether wasexposed to methyl acetoacetate in the presence of L3.Cu(OTf)₂ to afford5 (Scheme 3b). Although the intermediate oxocarbenium ion couldpotentially undergo both 1,2- and 1,4-addition, the 1,2-addition adduct5 was observed (as detected by NMR spectroscopy). Unfortunately,attempts to isolate 5 have been unsuccessful, due to facile eliminationof the □-methoxy group to form enone 6 (2.7:1 E/Z mixture).

The stereochemical model of the reaction with 1a, Cu(II)/BOX and DDQ isbased on a reported X-ray crystal structure of [L1.Cu(H₂O)₂](SbF₆)₂ byreplacement of H₂O ligands with the oxocarbenium ion of 1a (FIG. 1).¹⁹With the oxidized substrate bound to the Cu(II) center via bidentatechelation, the bulky tert-butyl group of the L3.Cu(II) complex shieldsthe top face of the bound substrate (Si face) which in turn places thetransient oxocarbenium ion below. During the reaction, the metal-boundenol(ate) adds to the Re face of the oxocarbenium ion via a pseudochair-like conformation to provide product 2a with S configuration atthe C1′ position, consistent with observed stereochemistry. This modelalso supports the observed relative C1′-C2′ trans relationship of theproducts.

A practical advantage of this strategy is the ease of syntheticallyelaborating these β-keto esters (Scheme 4). Conventional heating inDMF/H₂O provided the decarboxylated product 4 in 77% yield, wheremethylation of 2a gave 3,3-disubstituted tetrahydropyran-4-one 7 inexcellent yield with 13:1 dr. Exposure of β-ketoesters 2a or 7 toL-selectride provided the corresponding tetrahydropyran-4-ol 8 or 9,while LiAlH₄ reduction of 7 furnished diol 10.²⁰ Functionalization ofthe 6-position of the 7 has also been demonstrated. First, cyclic enone11 was prepared via dehydrogenation using 1 atm of O₂ in the presence ofPd(TFA)₂ in DMSO.²¹ Rh(I)-catalyzed 1,4-addition of phenylboronic acidproduced 12,²² and conjugate addition of an alkyl cuprate provided 13 asthe trans diastereomers in both reactions.^(20,23) Lastly,Mukaiyama-Michael addition proceeded to afford 14 with 10:1diasteromeric ratio.^(23,24) Notably, while many synthetic methods existfor cis-2,6-tetrahydropyran structures,²⁵ there are far fewerpreparations for trans-2,6-tetrahydropyrans.²⁶

To substitute DDQ as a reagent, we investigated complementary oxidationprocesses to form the oxocarbenium ion. A recent report of photoredoxcatalysis being used to generate oxocarbenium ions²⁷ inspired us toleverage this approach and trap the oxocarbenium ion with our tetheredcarbon nucleophile. Gratifyingly, the use of Sc(OTf)₃,Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆, blue LEDs, and bromochloroform providedaccess to rac-2a in 90% yield (Scheme 5). To date, these photoredoxconditions are not yet compatible with various chiral ligands to induceenantioselectivity.²⁸

In summary, a chiral Lewis acid-catalyzed intramolecularcross-dehydrogenative coupling of β-ketoesters has been developed. Thisoxidative process utilizes unfunctionalized starting materials toprovide chiral 2-substituted tetrahydropyrans with excellent yields andstereoselectivity. The in situ generation of both nucleophilic andelectrophilic partners specifically provides new opportunities forenantioselective oxocarbenium ion-driven reactions and CDC processes ingeneral. Investigations in our laboratory towards leveraging this chiralLewis acid/oxidation system with new substrate classes as well as theuse of visible light mediated oxidation in asymmetric transformationsare currently underway.

Materials and Methods

1. General Information

All reactions were carried out under a nitrogen atmosphere in oven-driedglassware with magnetic stirring. All organic solvents were purified bypassage through a bed of activated alumina. (See Pangborn, A. B.;Giardelo, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.Organometallics 1996, 15, 1518). Purification of reaction products wascarried out by flash chromatography using EM Reagent or Silicycle silicagel 60 (230-400 mesh). Analytical thin layer chromatography wasperformed on EM Reagent 0.25 mm silica gel 60-F plates. Visualizationwas accomplished with UV light and ceric ammonium nitrate stain,potassium permanganate stain or ninhydrin stain followed by heating. 1HNMR spectroscopy spectra were recorded on a Bruker Avance III 400 or 500MHz w/direct cryoprobe (400 or 500 MHz) spectrometer and are reported inppm using solvent as an internal standard (CDCl₃ at 7.26 ppm). Data arereported as (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,br=broad; coupling constant(s) in Hz, integration). Proton-decoupled 13CNMR spectroscopy spectra were recorded on a Bruker Avance 500 MHz w/direct cryoprobe (125 MHz) spectrometer and are reported in ppm usingsolvent as an internal standard (CDCl₃ at 77.16 ppm). SFC analysis wasperformed on an Agilent 1290 Infinity, using Chiralpak IA-3, IB-3, IC-3,ID-3, and IG-3 columns. Mass spectra data were obtained on a Varian 1200Quadrupole Mass Spectrometer and Micromass Quadro II Spectrometer or aWATERS Acquity-H UPLC-MS with a signal quad detector (ESI). L.Cu(OTf)₂complexes were prepared according to literature procedures. (See Evans,D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos, K. R.;Woerpel, K. A. J. Org. Chem. 1998, 63, 4541). Stereochemical models wereoptimized using the Spartan 08 program implement of semi-empirical PM3calculation. (See Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209).

2. General Procedure for Synthesis of β-Keto Esters (1

Acrylonitrile (0.39 mL, 6.0 mmol) was added to a mixture of thecorresponding cinnamyl alcohol (5.0 mmol) and 50 μL of aqueous NaOH(40%) at room temperature (If the corresponding cinnamyl alcohol wassolid, 2 mL of benzene or THF was added). The reaction mixture wasstirred for 15 h at same temperature, then neutralized with aqueous HCl(1 N), and diluted with ethyl acetate. The organic layer was washed with5% aqueous NaOH followed by brine, evaporated in vacuo, and driedthoroughly to afford the desired compound. The crude compound was usedfor the next steps without purification. (See Krishna, T. R.; Jayaraman,N, J. Org. Chem. 2003, 68, 9694).

To an oven dried 100 mL 3 neck round bottom flask equipped with a refluxcondenser under N₂ was added a magnetic stir bar, Zinc (1.63 g, 25mmol), and 15 mL of THF. The solution was heated to reflux, and then0.25 mL of methyl bromoacetate was added slowly to activate the zinc(gray color to hunter green). Once the zinc was activated, thecorresponding nitrile was added, followed by slow addition of 1.87 mL ofmethyl bromoacetate (20 mmol) over 1 h. The reaction stirred for 2 h,and was then removed from heat. The saturated NaHCO₃ solution was addedto quench the reaction, followed by addition of diethyl ether. Theheterogeneous solution was filtered over a pad of Celite with diethylether. The aqueous layer was extracted with diethyl ether, dried andconcentrated in vacuo. The 2.86 mL of AcOH (50 mmol), 10 mL of THF, and10 mL of H₂O were added to the crude compound. The reaction stirred for1 h at ambient temperature, and then saturated NaHCO₃ solution was addedto quench the reaction. The aqueous layer was extracted with ethylacetate, dried and concentrated in vacuo. The resulting residue waspurified by column chromatography on silica gel (hexanes:EtOAc=4:1) togive the corresponding β-keto esters 1. (The β-keto esters 1 wereisolated with the corresponding enol tautomer in 11:1 ratio.)

Yellow oil. (931.2 mg, 71% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.07 (s, 0.1H, enol),7.41-7.35 (m, 2H, keto+enol), 7.34-7.28 (m, 2H, keto+enol), 7.26-7.21(m, 1H, keto+enol), 6.59 (d, J=15.9 Hz, 1H, keto+enol), 6.25 (dt,J=15.9, 6.1 Hz, 1H, keto+enol), 5.10 (s, 0.1H, enol), 4.13 (dd, J=6.1,1.5 Hz, 2H, keto+enol), 3.75 (t, J=6.2 Hz, 2H, keto+enol), 3.73 (s, 3H,keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 1.8H, keto), 2.52(t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.0, 167.6,136.7, 136.7, 132.7, 132.6, 128.6, 127.2, 126.6, 126.5, 125.9, 125.7,90.2, 71.8, 71.7, 66.4, 64.9, 52.4, 51.2, 49.6, 43.2, 35.8.

HRMS (ESI) calculated for C₁₅H₁₈O₄ [M+Na]⁺: 285.110. Found: 285.109.

Yellow oil. (1.08 g, 78% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.15 (s, 0.1H, enol), 7.38(d, J=7.5 Hz, 2H, keto+enol), 7.31 (t, J=7.6 Hz, 2H, keto+enol), 7.24(t, J=7.3 Hz, 1H, keto+enol), 6.59 (d, J=15.9 Hz, 1H, keto+enol), 6.26(dt, J=15.9, 6.1 Hz, 1H, keto+enol), 5.08 (s, 0.1H, enol), 4.19 (q,J=7.2 Hz, 2H, keto+enol), 4.14 (dd, J=6.1, 1.4 Hz, 2H, keto+enol), 3.76(t, J=6.2 Hz, 1.8H, keto), 3.72 (t, J=6.4 Hz, 0.2H, enol), 3.50 (s,1.8H, keto), 2.84 (t, J=6.2 Hz, 1.8H, keto), 2.52 (t, J=6.5 Hz, 0.2H,enol), 1.27 (t, J=7.1 Hz, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.5, 175.6, 172.7, 167.2,136.7, 132.8, 132.7, 128.7, 127.9, 127.8, 126.6, 125.9, 125.8, 90.5,71.9, 71.7, 66.5, 65.0, 61.5, 60.2, 49.9, 43.2, 35.8, 14.4, 14.2.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1260.

Colorless oil. (1.02 g, 67% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.29 (s, 0.1H, enol), 7.38(d, J=7.5 Hz, 2H, keto+enol), 7.31 (t, J=7.6 Hz, 2H, keto+enol), 7.24(t, J=7.3 Hz, 1H, keto+enol), 6.59 (d, J=15.9 Hz, 1H, keto+enol), 6.26(dt, J=15.9, 6.1 Hz, 1H, keto+enol), 4.98 (s, 0.1H, enol), 4.14 (dd,J=6.1, 1.5 Hz, 2H, keto+enol), 3.76 (t, J=6.3 Hz, 1.8H, keto), 3.71 (t,J=6.6 Hz, 0.2H, enol), 3.41 (s, 1.8H, keto), 2.83 (t, J=6.3 Hz, 1.8H,keto), 2.49 (t, J=6.6 Hz, 0.2H, enol), 1.49 (s, 0.9H, enol), 1.47 (s,8.1H, keto).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.9, 174.9, 172.7, 166.4,136.7, 132.7, 132.6, 128.7, 127.8, 126.6, 126.0, 125.9, 91.9, 82.1,81.0, 71.9, 71.7, 66.5, 65.0, 51.2, 43.1, 35.8, 28.4, 28.1.

HRMS (ESI) calculated for C₁₈H₂₄O₄[M+Na]⁺: 327.1572. Found: 327.1577.

Colorless oil. (879.8 mg, 52% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol),7.40-7.29 (m, 8H, keto+enol), 7.27-7.22 (m, 1H, keto+enol), 6.59 (d,J=15.9 Hz, 1H, keto+enol), 6.24 (dt, J=15.9, 6.1 Hz, 1H, keto+enol),5.18 (s, 2H, keto+enol), 5.12 (s, 0.1H, enol), 4.16 (dd, J=6.0, 1.5 Hz,0.2H, enol), 4.12 (dd, J=6.1, 1.5 Hz, 1.8H, keto), 3.75 (t, J=6.2 Hz,1.8H, keto), 3.73-3.70 (m, 0.2H, enol), 3.57 (s, 1.8H, keto), 2.82 (t,J=6.2 Hz, 1.8H, keto), 2.53 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 176.2, 172.5, 167.0,136.7, 135.4, 132.8, 132.7, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3,127.9, 126.7, 125.8, 90.4, 71.9, 71.8, 67.3, 66.4, 65.9, 65.0, 49.9,43.3, 35.9.

HRMS (ESI) calculated for C₂₁H₂₂O₄[M+Na]⁺: 361.1416. Found: 361.1418.

Orange oil. (185.0 mg, 12% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm 16.13 (s, 1H), 7.88 (d, J=6.9 Hz, 2H),7.52 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.7 Hz, 2H), 7.37 (d, J=7.5 Hz, 2H),7.30 (t, J=7.6 Hz, 2H), 7.24 (t, J=7.3 Hz, 1H), 6.62 (d, J=15.9 Hz, 1H),6.33-6.24 (m, 2H), 4.19 (dd, J=6.0, 1.4 Hz, 2H), 3.84 (t, J=6.3 Hz, 2H),2.75 (t, J=6.4 Hz, 2H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 194.6, 183.3, 136.8, 134.9, 132.8,132.5, 128.8, 128.7, 127.9, 127.2, 126.7, 125.9, 97.0, 71.9, 66.2, 40.0.

HRMS (ESI) calculated for C₂₀H₂₀O₃[M+Na]⁺: 331.1310. Found: 331.1311.

Colorless oil. (1.04 g, 71% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.05 (s, 0.1H, enol), 7.31(d, J=8.7 Hz, 2H, keto+enol), 6.85 (d, J=8.7 Hz, 2H, keto+enol), 6.53(d, J=15.9 Hz, 1H, keto+enol), 6.11 (dt, J=15.9, 6.3 Hz, 1H, keto+enol),5.09 (s, 0.1H, enol), 4.11 (dd, J=6.2, 1.4 Hz, 2H, keto+enol), 3.80 (s,3H, keto+enol), 3.77-3.67 (m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.82(t, J=6.2 Hz, 1.8H, keto), 2.51 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6,159.5, 132.6, 132.5, 129.4, 127.8, 123.6, 123.4, 114.1, 90.2, 72.1,71.9, 66.3, 64.8, 55.4, 52.5, 51.3, 49.6, 43.3, 35.8.

HRMS (ESI) calculated for C16H₂₀O₅ [M+Na]⁺: 315.121. Found: 315.122.

Yellow oil. (1.13 g, 77% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.23(t, J=7.9 Hz, 1H, keto+enol), 6.98 (d, J=7.6 Hz, 1H, keto+enol), 6.92(s, 1H, keto+enol), 6.80 (dd, J=8.2, 1.9 Hz, 1H, keto+enol), 6.56 (d,J=15.9 Hz, 1H, keto+enol), 6.25 (dt, J=15.9, 6.1 Hz, 1H, keto+enol),5.09 (s, 0.1H, enol), 4.14 (dd, J=6.0, 1.5 Hz, 2H, keto+enol), 3.81 (s,3H, keto+enol), 3.79-3.72 (m, 5H, keto+enol), 3.53 (s, 1.8H, keto), 2.83(t, J=6.1 Hz, 1.8H, keto), 2.52 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.37, 167.63, 159.94,139.67, 138.19, 132.67, 129.78, 129.68, 129.59, 126.29, 126.14, 120.03,119.34, 118.03, 113.59, 113.54, 113.10, 111.90, 111.26, 90.26, 71.86,70.39, 66.49, 65.01, 55.36, 52.51, 52.07, 49.69, 43.28, 35.85.

HRMS (ESI) calculated for C₁₆H₂₀O₅ [M+Na]⁺: 315.121. Found: 315.122.

Colorless oil. (1.02 g, 70% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.05 (s, 0.1H, enol), 7.43(dd, J=7.6, 1.8 Hz, 1H, keto+enol), 7.25-7.20 (m, 1H, keto+enol),6.97-6.82 (m, 3H, keto+enol), 6.27 (dt, J=16.1, 6.2 Hz, 1H, keto+enol),5.09 (s, 0.1H, enol), 4.14 (dd, J=6.2, 1.5 Hz, 1.8H, keto+enol), 3.84(s, 3H, keto+enol), 3.79-3.69 (m, 5H, keto+enol), 3.53 (s, 1.8H, keto),2.82 (t, J=6.2 Hz, 1.8H, keto), 2.52 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.5, 175.9, 173.1, 167.7,156.9, 129.4, 128.9, 128.9, 127.9, 127.8, 127.1, 127.1, 126.5, 126.4,126.3, 125.8, 125.7, 120.8, 120.7, 110.9, 90.2, 72.4, 72.3, 66.3, 64.9,64.4, 55.5, 52.5, 51.3, 49.6, 43.3, 35.8.

HRMS (ESI) calculated for C₁₆H₂₀O₅ [M+Na]⁺: 315.1208. Found: 315.1213.

Pale yellow oil. (994.8 mg, 72% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.28(d, J=8.0 Hz, 2H, keto+enol), 7.12 (d, J=7.9 Hz, 2H, keto+enol), 6.56(d, J=15.9 Hz, 1H, keto+enol), 6.20 (dt, J=15.9, 6.2 Hz, 1H, keto+enol),5.09 (s, 0.1H, enol), 4.12 (dd, J=6.2, 1.5 Hz, 2H, keto+enol), 3.82-3.68(m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 2H, keto),2.51 (t, J=6.5 Hz, 0.2H, enol), 2.33 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6,137.7, 137.7, 133.9, 132.8, 132.7, 129.4, 126.5, 124.8, 124.7, 90.2,72.0, 71.9, 66.4, 64.9, 52.5, 51.3, 49.7, 43.3, 35.8, 21.3.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1269.

Pale yellow oil. (953.3 mg, 69% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol),7.24-7.16 (m, 3H, keto+enol), 7.10-7.04 (m, 1H, keto+enol), 6.56 (d,J=15.9 Hz, 1H, keto+enol), 6.24 (dt, J=15.9, 6.1 Hz, 1H, keto+enol),5.10 (s, 0.1H, enol), 4.13 (dd, J=6.1, 1.5 Hz, 2H, keto+enol), 3.82-3.66(m, 5H, keto+enol), 3.53 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 1.8H,keto), 2.52 (t, J=6.5 Hz, 0.2H, enol), 2.34 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6,138.2, 136.6, 132.9, 132.8, 131.3, 128.7, 128.6, 128.6, 128.5, 127.4,127.3, 125.7, 125.6, 123.8, 123.7, 90.2, 71.9, 64.9, 52.5, 49.7, 43.3,21.5.

HRMS (ESI) calculated for C₁₆H₂₀O₄[M+Na]⁺: 299.1259. Found: 299.1263.

Yellow oil. (994.6 mg, 72% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.07 (s, 0.1H, enol),7.47-7.41 (m, 1H, keto+enol), 7.19-7.11 (m, 3H, keto+enol), 6.81 (d,J=15.8 Hz, 1H, keto+enol), 6.14 (dt, J=15.8, 6.1 Hz, 1H, keto+enol),5.10 (s, 0.1H, enol), 4.16 (dd, J=6.1, 1.5 Hz, 2H, keto+enol), 3.77 (t,J=6.2 Hz, 2H, keto+enol), 3.73 (s, 3H, keto+enol), 3.53 (s, 1.8H, keto),2.84 (t, J=6.2 Hz, 1.8H, keto), 2.53 (t, J=6.5 Hz, 0.2H, enol), 2.35 (s,3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6,135.8, 135.6, 130.6, 130.5, 130.4, 127.8, 127.7, 127.2, 127.1, 126.2,125.9, 90.2, 72.1, 71.9, 66.4, 64.9, 52.5, 51.3, 49.7, 43.3, 35.9, 19.9.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1265.

Colorless oil. (1.25 g, 73% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.43(d, J=8.5 Hz, 2H, keto+enol), 7.24 (d, J=8.4 Hz, 2H, keto+enol), 6.52(d, J=16.0 Hz, 1H, keto+enol), 6.24 (dt, J=16.0, 5.9 Hz, 1H, keto+enol),5.09 (s, 0.1H, enol), 4.11 (dd, J=6.0, 1.5 Hz, 2H, keto+enol), 3.79-3.67(m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.1 Hz, 1.8H,keto), 2.51 (t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.0, 167.6,135.7, 131.8, 131.4, 131.3, 128.1, 126.8, 126.7, 121.6, 90.3, 71.7,71.5, 66.6, 65.1, 52.5, 51.3, 49.7, 43.2, 35.8.

HRMS (ESI) calculated for C₁₅H₁₇BrO₄[M+Na]⁺: 363.0208. Found: 363.0213.

Yellow oil. (1.28 g, 75% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.52(s, 1H, keto+enol), 7.36 (d, J=7.9 Hz, 1H, keto+enol), 7.28 (d, J=7.7Hz, 1H, keto+enol), 7.17 (t, J=7.8 Hz, 1H, keto+enol), 6.52 (d, J=15.9Hz, 1H, keto+enol), 6.25 (dt, J=15.9, 5.9 Hz, 1H, keto+enol), 5.09 (s,OH, enol), 4.13 (dd, J=5.8, 1.6 Hz, 2H, keto+enol), 3.81-3.67 (m, 5H,keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 1.8H, keto), 2.51(t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.0, 167.6,138.9, 131.0, 1309, 130.7, 130.6, 130.3, 130.2, 129.5, 127.5, 125.2,122.9, 90.3, 71.5, 71.4, 65.1, 64.9, 52.5, 52.0, 49.7, 43.2, 35.8.

HRMS (ESI) calculated for C₁₅H₁₇BrO₄[M+Na]⁺: 363.0208. Found: 363.0204.

Yellow oil. (1.13 g, 76% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.36(s, 1H, keto+enol), 7.25-7.17 (m, 3H, keto+enol), 6.53 (d, J=15.9 Hz,1H, keto+enol), 6.26 (dt, J=15.9, 5.9 Hz, 1H, keto+enol), 5.09 (s, 0.1H,enol), 4.13 (dd, J=5.8, 1.5 Hz, 2H, keto+enol), 3.80-3.68 (m, 5H,keto+enol), 3.52 (s, 1.8H, keto), 2.83 (t, J=6.2 Hz, 1.8H, keto), 2.51(t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.1, 167.6,138.6, 134.6, 131.1, 131.0, 129.9, 129.8, 128.0, 127.8, 127.7, 127.6,127.4, 126.6, 124.8, 90.3, 71.6, 71.4, 65.3, 65.1, 52.5, 51.3, 49.7,43.2, 35.8.

HRMS (ESI) calculated for C₁₅H₁₇ClO₄ [M+Na]⁺: 319.0713. Found: 319.0714.

Pale yellow oil. (1.04 g, 70% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.53(dd, J=7.6, 1.8 Hz, 1H, keto+enol), 7.34 (dd, J=7.7, 1.6 Hz, 1H,keto+enol), 7.22 (td, J=7.5, 1.6 Hz, 1H, keto+enol), 7.18 (td, J=7.6,1.8 Hz, 1H, keto+enol), 6.98 (d, J=15.9 Hz, 1H, keto+enol), 6.24 (dt,J=16.0, 5.9 Hz, 1H, keto+enol), 5.10 (s, 0.1H, enol), 4.17 (dd, J=6.0,1.6 Hz, 2H, keto+enol), 3.78 (t, J=6.1 Hz, 2H, keto+enol), 3.73 (s, 3H,keto+enol), 3.53 (s, 1.8H, keto), 2.84 (t, J=6.1 Hz, 1.8H, keto), 2.53(t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.7, 173.1, 167.6,134.9, 133.2, 131.6, 129.8, 128.9, 128.8, 128.7, 128.7, 127.2, 127.1,127.1, 127.0, 90.3, 71.8, 71.6, 66.6, 65.1, 63.8, 52.5, 51.3, 49.7,43.3, 35.8.

HRMS (ESI) calculated for C₁₅H₁₇ClO₄ [M+Na]⁺: 319.0713. Found: 319.0710.

Colorless oil. (1.11 g, 71% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.09 (s, 0.1H, enol),7.86-7.76 (m, 3H, keto+enol), 7.74 (s, 1H, keto+enol), 7.60 (dd, J=8.5,1.8 Hz, 1H, keto+enol), 7.52-7.40 (m, 2H, keto+enol), 6.76 (d, J=15.9Hz, 1H, keto+enol), 6.39 (dt, J=16.0, 6.1 Hz, 1H, keto+enol), 5.12 (s,0.1H, enol), 4.20 (dd, J=6.0, 1.5 Hz, 2H, keto+enol), 3.80 (t, J=6.2 Hz,2H, keto+enol), 3.74 (s, 3H, keto+enol), 3.54 (s, 1.8H, keto), 2.85 (t,J=6.2 Hz, 1.8H, keto), 2.55 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6,134.2, 133.7, 133.2, 132.8, 132.8, 128.3, 128.1, 128.0, 127.8, 127.8,126.7, 126.4, 126.3, 126.2, 126.1, 126.0, 123.7, 90.3, 72.0, 71.8, 65.1,65.0, 52.5, 51.3, 49.7, 43.3, 35.9.

HRMS (ESI) calculated for C₁₉H₂₀O₄ [M+Na]⁺: 335.1259. Found: 335.1258.

Yellow oil. (1.08 g, 69% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.11 (s, 0.1H, enol),8.18-8.03 (m, 1H, keto+enol), 7.89-7.82 (m, 1H, keto+enol), 7.79 (d,J=8.2 Hz, 1H, keto+enol), 7.61 (d, J=7.1 Hz, 1H, keto+enol), 7.55-7.47(m, 2H, keto+enol), 7.47-7.43 (m, 1H, keto+enol), 7.36 (d, J=15.7 Hz,1H, keto+enol), 6.30 (dt, J=15.7, 5.9 Hz, 1H, keto+enol), 5.14 (s, 0.1H,enol), 4.26 (dd, J=5.9, 1.6 Hz, 2H, keto+enol), 3.84 (t, J=6.2 Hz, 1.8H,keto), 3.80 (t, J=6.4 Hz, 0.2H, enol), 3.74 (s, 3H, keto+enol), 3.55 (s,1.8H, keto), 2.87 (t, J=6.1 Hz, 1.8H, keto), 2.57 (t, J=6.4 Hz, 0.2H,enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.4, 175.8, 173.1, 167.6, 134.5,133.7, 131.3, 129.8, 129.6, 129.2, 129.1, 128.6, 128.2, 128.2, 126.2,125.9, 125.7, 124.1, 124.1, 123.9, 90.3, 72.0, 71.9, 66.5, 65.1, 52.5,51.3, 49.7, 43.3, 35.9.

HRMS (ESI) calculated for C₁₉H₂₀O₄ [M+Na]⁺: 335.1259. Found: 335.1257.

Yellow oil. (967.2 mg, 70% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.04 (s, 0.1H, enol), 7.30(t, J=7.5 Hz, 2H, keto+enol), 7.27-7.23 (m, 2H, keto+enol), 7.19 (t,J=7.2 Hz, 1H, keto+enol), 6.45 (s, 1H, keto+enol), 5.08 (s, 0.1H, enol),4.01 (s, 0.2H, enol), 3.99 (s, 1.8H, keto), 3.75-3.63 (m, 5H,keto+enol), 3.51 (s, 1.8H, keto), 2.81 (t, J=6.1 Hz, 1.8H, keto), 2.50(t, J=6.4 Hz, 0.2H, enol), 1.84 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.9, 173.0, 167.6,137.5, 137.5, 135.1, 135.0, 129.0, 129.0, 128.2, 127.2, 127.1, 126.6,126.6, 90.2, 77.4, 77.2, 66.1, 64.8, 52.4, 51.2, 49.7, 43.2, 35.8, 15.5.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1254.

Yellow oil. (1.68 g, 74% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.08 (s, 0.1H, enol), 7.98(d, J=8.3 Hz, 1H, keto+enol), 7.75 (d, J=8.4 Hz, 2H, keto+enol), 7.72(d, J=7.9 Hz, 1H, keto+enol), 7.59 (s, 1H, keto+enol), 7.36-7.30 (m, 1H,keto+enol), 7.29-7.24 (m, 1H, keto+enol), 7.20 (d, J=8.2 Hz, 2H,keto+enol), 6.66 (d, J=16.2 Hz, 1H, keto+enol), 6.32 (dt, J=16.1, 6.0Hz, 1H, keto+enol), 5.11 (s, 0.1H, enol), 4.15 (dd, J=6.1, 1.5 Hz, 1H,keto+enol), 3.77 (t, J=6.2 Hz, 1H, keto+enol), 3.73 (s, 3H, keto+enol),3.53 (s, 1.8H, keto), 2.84 (t, J=6.1 Hz, 1.8H, keto), 2.53 (t, J=6.5 Hz,0.2H, enol), 2.32 (s, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.1, 167.6,145.2, 135.6, 135.2, 130.0, 129.1, 127.2, 127.0, 127.0, 125.1, 124.3,124.3, 123.6, 123.4, 123.2, 120.5, 120.1, 113.9, 90.3, 72.1, 71.9, 66.5,65.0, 52.5, 51.3, 49.7, 43.2, 35.8, 21.7.

HRMS (ESI) calculated for C₂₄H₂₅NO₆S [M+Na]⁺: 478.1300. Found: 478.1308.

Yellow oil. (1.01 g, 76% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.05 (s, 0.1H, enol),7.18-7.14 (m, 1H, keto+enol), 6.98-6.93 (m, 2H, keto+enol), 6.71 (d,J=15.7 Hz, 1H, keto+enol), 6.08 (dt, J=15.7, 6.1 Hz, 1H, keto+enol),5.09 (s, 0.1H, enol), 4.09 (dd, J=6.1, 1.5 Hz, 2H, keto+enol), 3.79-3.71(m, 5H, keto+enol), 3.52 (s, 1.8H, keto), 2.82 (t, J=6.2 Hz, 1.8H,keto), 2.51 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.7, 173.1, 167.6,141.8, 127.5, 126.0, 126.0, 125.9, 125.8, 125.5, 125.4, 124.6, 124.6,90.2, 71.5, 71.4, 66.5, 65.0, 52.5, 51.3, 49.7, 43.2, 35.8.

HRMS (ESI) calculated for C₁₃H₁₆O₄S [M+Na]⁺: 291.0667. Found: 291.0662.

Yellow oil. (1.10 g, 76% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol), 7.39(d, J=7.4 Hz, 2H, keto+enol), 7.31 (t, J=7.6 Hz, 2H, keto+enol), 7.22(t, J=7.3 Hz, 1H, keto+enol), 6.77 (dd, J=15.6, 10.5 Hz, 1H, keto+enol),6.55 (d, J=15.7 Hz, 1H, keto+enol), 6.40 (dd, J=15.0, 10.7 Hz, 1H,keto+enol), 5.85 (dt, J=15.2, 6.2 Hz, 1H, keto+enol), 5.09 (s, 0.1H,enol), 4.06 (dd, J=6.3, 1.4 Hz, 2H, keto+enol), 3.78-3.67 (m, 5H,keto+enol), 3.52 (s, 1.8H, keto), 2.82 (t, J=6.2 Hz, 1.8H, keto), 2.51(t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.1, 167.6,137.2, 133.2, 133.2, 133.0, 133.0, 129.9, 129.7, 128.7, 128.3, 128.2,127.8, 126.5, 90.2, 71.6, 71.4, 65.3, 65.0, 52.5, 51.3, 49.7, 43.3,35.8, 15.2.

HRMS (ESI) calculated for C₁₇H₂₀O₄ [M+Na]⁺: 311.1259. Found: 311.1256.

Pale yellow oil. (998.6 mg, 75% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.03 (s, 0.1H, enol), 7.23(d, J=8.6 Hz, 2H, keto+enol), 6.87 (d, J=8.7 Hz, 2H, keto+enol), 5.06(s, 0.1H, enol), 4.45 (s, 0.2H, enol), 4.43 (s, 1.8H, keto), 3.79 (s,3H, keto+enol), 3.74-3.69 (m, 5H, keto+enol), 3.49 (s, 1.8H, keto), 2.80(t, J=6.2 Hz, 1.8H, keto), 2.49 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.9, 173.0, 167.6,159.4, 130.1, 129.5, 129.4, 113.9, 90.1, 73.0, 72.8, 66.1, 64.8, 55.4,52.4, 51.2, 49.6, 43.3, 35.8.

HRMS (ESI) calculated for C₁₄H₁₈O₅ [M+Na]⁺: 289.1052. Found: 289.1046.

Yellow oil. (1.13 g, 76% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.04 (s, 0.1H, enol),6.88-6.78 (m, 3H, keto+enol), 5.07 (s, 0.1H, enol), 4.45 (s, 0.2H,enol), 4.43 (s, 1.8H, keto), 3.88 (s, 3H, keto+enol), 3.86 (s, 3H,keto+enol), 3.74-3.64 (m, 5H, keto+enol), 3.49 (s, 1.8H, keto), 2.80 (t,J=6.1 Hz, 1.8H, keto), 2.49 (t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 175.9, 173.0, 167.6,149.1, 148.8, 130.6, 120.4, 120.3, 111.1, 111.0, 111.0, 110.9, 90.1,73.3, 73.1, 66.1, 64.8, 56.0, 55.9, 55.8, 52.4, 51.2, 49.6, 43.2, 35.7.

HRMS (ESI) calculated for C₁₅H₂₀O₆[M+Na]⁺: 319.1158. Found: 319.1154.

Yellow oil. (1.19 g, 73% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.05 (s, 0.1H, enol), 6.53(s, 2H, keto+enol), 5.08 (s, 0.1H, enol), 4.44 (s, 0.2H, enol), 4.42 (s,1.8H, keto), 3.84 (s, 6H, keto+enol), 3.81 (s, 3H, keto+enol), 3.74 (t,J=6.1 Hz, 2H, keto+enol), 3.70 (s, 3H, keto+enol), 3.49 (s, 1.8H, keto),2.82 (t, J=6.1 Hz, 1.8H, keto), 2.51 (t, J=6.3 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.2, 175.8, 173.0, 167.5,153.4, 137.5, 137.4, 133.8, 133.7, 90.2, 73.5, 73.3, 66.4, 65.0, 60.9,56.1, 56.1, 52.4, 51.2, 49.6, 43.1, 35.7.

HRMS (ESI) calculated for C₁₆H₂₂O₇ [M+Na]⁺: 349.1263. Found: 349.1259.

Colorless oil. (967.0 mg, 70% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.03 (s, 0.1H, enol), 7.39(d, J=7.6 Hz, 2H, keto+enol), 7.32 (t, J=7.6 Hz, 2H, keto+enol), 7.24(t, J=7.9 Hz, 1H, keto+enol), 6.52 (d, J=16.0 Hz, 1H, keto+enol), 6.08(dd, J=16.0, 7.7 Hz, 1H, keto+enol), 5.08 (s, 0.1H, enol), 4.00 (p,J=6.6 Hz, 1H, keto+enol), 3.77 (dt, J=9.7, 6.2 Hz, 1H, keto+enol), 3.73(s, 3H, keto+enol), 3.63 (dt, J=9.7, 6.3 Hz, 1H, keto+enol), 3.52 (s,1.8H, keto), 2.84-2.73 (m, 1.8H, keto), 2.49 (t, J=6.6 Hz, 0.2H, enol),1.31 (d, J=6.4 Hz, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.6, 176.0, 173.1, 167.7,136.6, 131.6, 131.5, 131.4, 131.3, 128.7, 127.8, 126.6, 90.1, 77.2,77.0, 64.6, 63.2, 52.4, 51.2, 49.7, 43.5, 36.0, 21.7.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1255.

Yellow oil. (885.0 mg, 68% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.06 (s, 0.1H, enol),7.47-7.42 (m, 2H, keto+enol), 7.34-7.28 (m, 3H, keto+enol), 5.11 (s,0.1H, keto+enol), 4.38 (s, 0.2H, enol), 4.36 (s, 1.8H, keto), 3.86 (t,J=6.1 Hz, 1.8H, keto), 3.82 (t, J=6.4 Hz, 0.2H, enol), 3.72 (s, 3H,keto+enol), 3.53 (s, 1.8H, keto), 2.85 (t, J=6.2 Hz, 1.8H, keto), 2.54(t, J=6.4 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.1, 175.5, 173.0, 167.6,131.9, 131.8, 128.6, 128.6, 128.5, 128.4, 122.6, 122.6, 90.2, 86.6,86.6, 84.9, 84.8, 66.1, 64.7, 59.3, 59.1, 52.5, 51.3, 49.5, 43.1, 35.5.

HRMS (ESI) calculated for C1411604 [M+Na]⁺: 283.0946. Found: 283.0943.

Pale yellow oil. (689.0 mg, 74% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.02 (s, 0.1H, enol),5.91-5.80 (m, 1H, keto+enol), 5.24 (dd, J=17.2, 1.7 Hz, 1H, keto+enol),5.16 (dd, J=10.4, 1.6 Hz, 1H, keto+enol), 5.05 (s, 0.1H, enol), 3.95(dt, J=5.6, 1.5 Hz, 2H, keto+enol), 3.72 (s, 3H, keto+enol), 3.69 (t,J=6.2 Hz, 1.8H, keto), 3.64 (t, J=6.5 Hz, 0.2H, enol), 3.49 (s, 1.8H,keto), 2.79 (t, J=6.2 Hz, 1.8H, keto), 2.47 (t, J=6.5 Hz, 0.2H, enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 175.8, 173.0, 167.6,134.6, 134.5, 117.3, 117.3, 90.1, 72.2, 72.1, 66.4, 64.9, 52.4, 51.2,49.6, 43.2, 35.8.

HRMS (ESI) calculated for C₉H₁₄O₄ [M+Na]⁺: 209.0790. Found: 209.0782.

Colorless oil. (567.4 mg, 56% overall yield over 3 steps)

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 12.02 (s, 0.1H, enol), 5.06(s, 0.1H, enol), 3.73 (d, J=5.5 Hz, 3H, keto+enol), 3.67 (t, J=6.2 Hz,1.8H, keto), 3.63 (t, J=6.6 Hz, 0.2H, enol), 3.50 (s, 1.8H, keto), 3.40(t, J=6.6 Hz, 2H, keto+enol), 2.77 (t, J=6.2 Hz, 1.8H, keto), 2.47 (t,J=6.5 Hz, 0.2H, enol), 1.58-1.45 (m, 2H, keto+enol), 1.38-1.29 (m, 2H,keto+enol), 0.90 (t, J=7.4 Hz, 3H, keto+enol).

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.7, 176.1, 173.1, 167.7,90.0, 71.2, 71.0, 67.0, 65.6, 52.5, 52.4, 51.3, 50.0, 49.7, 43.3, 35.8,31.8, 30.3, 19.4, 14.0.

HRMS (ESI) calculated for C₁₀H₁₈O₄[M+Na]⁺: 225.1103. Found: 225.1100.

To a suspension of 60% NaH (264 mg, 6.6 mmol) in THF (20 mL) at 0° C.was added cinnamyl alcohol (492.5 mg, 3.0 mmol), and the resultingmixture was stirred at ambient temperature for 2 h. To this mixture wasthen added ethyl 4-chloroacetateacetate (0.41 mL, 3.0 mmol) dropwiseover 30 min, and the resulting clear yellow solution was stirred atambient temperature overnight before it was cooled to 5° C., acidifiedto pH=4 using 5% HCl and extracted with the EtOAc (2×25 mL). Thecombined organics were washed with brine, dried over MgSO₄, andconcentrated in vacuo. The resulting residue was purified by columnchromatography on silica gel (hexanes:EtOAc=10:1 to 4:1) to give thecorresponding β-keto esters 1x as colorless oil (605.9 mg, 77% yield).

¹H NMR (500 MHz, CDCl₃): δ ppm (keto+enol) 11.99 (s, 0.1H, enol), 7.39(d, J=7.3 Hz, 2H, keto+enol), 7.33 (t, J=7.5 Hz, 2H, keto+enol),7.29-7.22 (m, 1H, keto+enol), 6.62 (d, J=15.9 Hz, 1H, keto+enol), 6.26(dt, J=15.9, 6.2 Hz, 1H, keto+enol), 5.33 (s, 0.1H, enol), 4.23 (dd,J=6.2, 1.4 Hz, 2H, keto+enol), 4.21-4.16 (m, 4H, keto+enol), 3.54 (s,1.8H, keto), 1.26 (t, J=7.1 Hz, 3H, keto+enol).

LRMS (ESI) calculated for C₉H₁₄O₄[M+H]⁺: 263.1. Found: 263.1.

To an oven dried 250 mL round bottom flask equipped with a magnetic stirbar was added the 1a (786.9 mg, 3.0 mmol), 144.0 mg of NaH (60% in oil,3.6 mmol), and 40 mL of THF at 0° C. Methyl iodide (0.75 mL, 12.0 mmol)was added to the solution. The solution was stirred for 1 h at 0° C. andthen stirred for 14 h at ambient temperature additionally. The saturatedNH₄C1 solution was added to quench the reaction, followed by addition ofethyl acetate. The aqueous layer was extracted with ethyl acetate, driedand concentrated in vacuo. The crude was purified by silica gel columnchromatography with ethyl acetate/hexane (1:3) to give thea-methyl-β-keto ester 1z as colorless oil (503.0 mg, 61% yield).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.38 (d, J=7.9 Hz, 2H), 7.31 (t, J=7.5Hz, 2H), 7.26-7.21 (m, 1H), 6.59 (d, J=15.9 Hz, 1H), 6.25 (dtd, J=15.9,6.0, 1.0 Hz, 1H), 4.13 (d, J=6.1 Hz, 2H), 3.78-3.74 (m, 2H), 3.73 (d,J=1.1 Hz, 3H), 3.60 (qd, J=7.2, 0.9 Hz, 1H), 2.89-2.79 (m, 2H), 1.36(dd, J=7.2, 1.3 Hz, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 204.3, 171.0, 136.8, 132.7, 128.7,127.9, 126.6, 125.9, 71.9, 65.1, 53.3, 52.6, 41.7, 12.7.

HRMS (ESI) calculated for C₁₆H₂₀O₄ [M+Na]⁺: 299.1259. Found: 299.1257.

3. Optimization of Enantioselective CDC Reaction

entry deviation from standard condition yield (%) e.r. 1 none 65 92:8 2w/o pre-complexation between L1 and Cu(OTf)₂ 35~67 56:44~90:10 3 w/o MS4Å 10 87:13 4 MS 3Å instead of MS 4Å 68 90:10 5 ClCH₂CH₂Cl instead ofCH₂Cl₂ 68 90:10 6 MeCN instead of CH₂Cl₂ 45 74:26 7 CH₂Cl₂/MeCN insteadof CH₂Cl₂ 55 75:25 8 CH₂Cl₂/Toluene instead of CH₂Cl₂ 28 86:14 9CH₂Cl₂/THF instead of CH₂Cl₂ 10 85:15 10 Cl instead of OTf 45 52:48 11OAc instead of OTf 49 56:44 12 ClO₄ instead of OTf 65 69:31 13 SbF₆instead of OTf 68 74:26 14 PF₆ instead of OTf 70 81:19 15 BF₄ instead ofOTf 69 85:15

To an oven dried 20 mL reaction vial equipped with a magnetic stir barunder N₂ was added Na₂HPO₄ (56.8 mg, 0.4 mmol), 150 mg of 4 Å molecularsieve (powder), 1.0 mL of L1.Cu(OTf)₂ (0.02 M in CH₂Cl₂). The solutionthen was stirred for 1 h. The β-keto ester 1a was dissolved in 0.5 mL ofCH₂Cl₂ and was added, and the solution stirred at ambient temperaturefor 30 minutes. The reaction was then cooled to −30° C., and DDQ (59.0mg, 0.26 mmol) dissolved in 4.0 mL of DCM was added over 1 h by syringepump. The reaction was stirred for 2 h at −30° C., and then 1.0 mL ofEt₃N was added to quench the reaction. The solution was filtered over apad of silica (4 cm) with ethyl acetate and concentrated under reducedpressure. The crude was purified by silica gel column chromatographywith ethyl acetate/hexane (1:5) to give the tetrahydropyran-4-one 2a.

4. General Procedure for Enantioselective CDC Reaction

To an oven dried 20 mL reaction vial equipped with a magnetic stir barunder N₂ was added Na₂HPO₄ (56.8 mg, 0.4 mmol), 250 mg of 4 Å molecularsieve (powder), 1.0 mL of L3.Cu(OTf)₂ (0.02 M in CH₂Cl₂), and 4.0 mL ofCH₂Cl₂. The solution then was stirred for 1 h. The corresponding β-ketoester was dissolved in 1.0 mL of CH₂Cl₂ and was added, and the solutionstirred at ambient temperature for 30 mins. The reaction was then cooledto −70° C., and DDQ (59.0 mg, 0.26 mmol) dissolved in 4.0 mL of DCM wasadded over 1 h by syringe pump. The reaction was stirred for 12 h at−70° C., and then 1.0 mL of Et₃N was added to quench the reaction. Thesolution was filtered over a pad of silica (4 cm) with ethyl acetate andconcentrated under reduced pressure. The crude was purified by silicagel column chromatography with ethyl acetate/hexane (1:4˜1:6) to givethe corresponding tetrahydropyran-4-ones 2. (The tetrahydropyran-4-ones2 were isolated with the corresponding enol tautomers 2′.)

White solid. (43.3 mg, 83% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.39-7.36 (m, 2H), 7.35-7.30 (m, 2H),7.29-7.25 (m, 1H), 6.72 (d, J=15.9 Hz, 1H), 6.17 (dd, J=15.9, 6.6 Hz,1H), 4.58 (dd, J=10.1, 6.7 Hz, 1H), 4.38 (ddd, J=11.6, 7.3, 1.6 Hz, 1H),3.87 (td, J=11.9, 2.8 Hz, 1H), 3.74 (s, 3H), 3.48 (d, J=10.1 Hz, 1H),2.70 (ddd, J=14.4, 12.4, 7.3 Hz, 1H), 2.51 (dt, J=14.6, 2.0 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.3, 168.0, 136.1, 133.7, 128.8,128.5, 126.9, 125.8, 80.2, 66.5, 63.6, 52.4, 41.6.

HRMS (ESI) calculated for C1411604 [M+Na]⁺: 283.0946. Found: 283.0946.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 3.3 min (major), 2.9 min (minor).

Yellow solid. (38.5 mg, 70% yield, 89:11 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.40-7.35 (m, 2H), 7.32 (t, J=7.5 Hz,2H), 7.29-7.22 (m, 1H), 6.72 (d, J=15.9 Hz, 1H), 6.18 (dd, J=15.9, 6.6Hz, 1H), 4.63-4.51 (m, 1H), 4.37 (ddd, J=11.5, 7.3, 1.5 Hz, 1H),4.29-4.13 (m, 2H), 3.87 (td, J=11.9, 2.9 Hz, 1H), 3.45 (dd, J=10.2, 1.0Hz, 1H), 2.70 (ddd, J=14.5, 12.6, 7.6 Hz, 1H), 2.50 (ddd, J=14.6, 2.9,1.6 Hz, 1H), 1.24 (td, J=7.1, 5.1 Hz, 3H) for keto form; 12.29 (s, 1H),7.42-7.35 (m, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.29-7.22 (m, 1H), 6.51 (d,J=16.0 Hz, 1H), 6.29 (dd, J=16.0, 5.6 Hz, 1H), 5.11 (d, J=5.6 Hz, 1H),4.29-4.12 (m, 2H), 4.02-3.92 (m, 1H), 3.84-3.78 (m, 1H), 2.64-2.53 (m,1H), 2.28 (dt, J=17.9, 3.9 Hz, 1H), 1.24 (td, J=7.1, 5.1 Hz, 3H) forenol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 170.7, 170.7, 167.5,136.8, 136.1, 133.7, 133.1, 128.7, 128.7, 128.6, 128.4, 127.9, 126.9,126.7, 125.9, 99.3, 80.2, 71.2, 66.5, 63.6, 61.4, 60.6, 59.0, 41.6,29.1, 14.3, 14.3.

HRMS (ESI) calculated for C₁₆H₁₈O₄[M+Na]⁺: 297.1103. Found: 297.1105.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.9 min (minor), 3.2 min (major).

Colorless oil. (33.5 mg, 55% yield, 90:10 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.38 (t, J=6.4 Hz, 2H), 7.32 (t, J=7.5Hz, 2H), 7.29-7.22 (m, 1H), 6.71 (d, J=15.9 Hz, 1H), 6.19 (dd, J=15.9,6.6 Hz, 1H), 4.53 (ddd, J=10.1, 6.6, 0.9 Hz, 1H), 4.35 (ddd, J=11.5,7.3, 1.6 Hz, 1H), 3.85 (td, J=11.9, 2.9 Hz, 1H), 3.34 (d, J=10.7 Hz,4H), 2.73-2.63 (m, 1H), 2.47 (ddd, J=14.7, 2.9, 1.7 Hz, 1H), 1.45 (s,9H) for keto form; 12.43 (s, 1H), 7.38 (t, J=6.4 Hz, 2H), 7.32 (t, J=7.5Hz, 2H), 7.29-7.23 (m, 1H), 6.52 (d, J=15.9 Hz, 1H), 6.27 (dd, J=15.9,5.9 Hz, 1H), 5.02 (d, J=5.8 Hz, 1H), 4.00-3.92 (m, 1H), 3.82-3.75 (m,1H), 2.58-2.50 (m, 1H), 2.27 (dt, J=17.8, 3.9 Hz, 1H), 1.44 (s, 9H) forenol form.

HRMS (ESI) calculated for C₁₈H₂₂O₄ [M+Na]⁺: 325.1416. Found: 325.1410.

Chiral SFC (Chiralpak IB-3, 2% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.4 min (major), 2.8 min (minor).

White solid. (35.8 mg, 56% yield, 84:16 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.33-7.27 (m, 7H), 7.27-7.22 (m, 3H),6.65 (dd, J=15.9, 1.0 Hz, 1H), 6.13 (dd, J=15.9, 6.7 Hz, 1H), 5.19 (s,2H), 4.58 (dd, J=10.2, 6.7 Hz, 1H), 4.37 (ddd, J=11.4, 7.3, 1.2 Hz, 1H),3.87 (td, J=11.9, 2.8 Hz, 1H), 3.51 (d, J=10.3 Hz, 1H), 2.75-2.63 (m,1H), 2.50 (ddd, J=14.8, 2.8, 1.6 Hz, 1H).

HRMS (ESI) calculated for C₂₁H₂₀O₄ [M+Na]⁺: 359.1259. Found: 359.1260.

Chiral SFC (Chiralpak IB-3, 2% MeOH in CO₂, flow rate=2.5 mL/min, λ=210nm): 6.5 min (major), 6.8 min (minor).

White solid. (42.3 mg, 69% yield)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.84 (d, J=7.6 Hz, 2H), 7.55 (t, J=7.4Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.35-7.09 (m, 5H), 6.71 (d, J=15.9 Hz,1H), 6.13 (dd, J=16.0, 6.0 Hz, 1H), 4.89 (dd, J=9.7, 6.1 Hz, 1H),4.53-4.32 (m, 2H), 3.96 (td, J=11.9, 3.0 Hz, 1H), 2.89-2.76 (m, 1H),2.55 (d, J=14.7 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 203.7, 196.4, 137.6, 136.2, 133.7,133.2, 128.9, 128.7, 128.5, 128.2, 126.8, 126.3, 80.3, 66.4, 64.1, 42.3.

HRMS (ESI) calculated for C₂₀H₁₈O₃ [M+Na]⁺: 329.1154. Found: 329.1150.

Yellow solid. (34.8 mg, 60% yield, 78:22 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.31 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6Hz, 2H), 6.65 (d, J=15.9 Hz, 1H), 6.03 (dd, J=15.9, 6.8 Hz, 1H), 4.55(dd, J=9.8, 7.1 Hz, 1H), 4.37 (dd, J=10.9, 6.8 Hz, 1H), 3.85 (td,J=12.0, 2.6 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.47 (d, J=10.1 Hz,1H), 2.69 (td, J=13.4, 12.4, 7.4 Hz, 1H), 2.50 (d, J=14.4 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.4, 168.0, 159.9, 133.4, 128.8,128.2, 123.5, 114.2, 80.5, 66.4, 63.7, 55.5, 52.4, 41.6.

HRMS (ESI) calculated for C₁₆H₁₈O₅ [M+Na]⁺: 313.1052. Found: 313.1055.

Chiral SFC (Chiralpak IG-3, 5% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 9.1 min (major), 8.5 min (minor).

Yellow oil. (45.1 mg, 78% yield, 96:4 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.24 (t, J=7.9 Hz, 1H), 6.98 (ddt, J=9.0,7.7, 1.2 Hz, 1H), 6.92 (dt, J=11.9, 2.0 Hz, 1H), 6.82 (tdd, J=8.1, 2.6,0.9 Hz, 1H), 6.68 (d, J=15.9 Hz, 1H), 6.16 (dd, J=15.9, 6.6 Hz, 1H),4.58 (dd, J=10.6, 7.0 Hz, 1H), 4.38 (ddd, J=11.6, 7.3, 1.7 Hz, 1H),3.90-3.84 (m, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.47 (d, J=10.2 Hz, 1H),2.76-2.65 (m, 1H), 2.54-2.45 (m, 1H) for keto form; 12.21 (s, 1H), 7.24(t, J=7.9 Hz, 1H), 6.98 (ddt, J=9.0, 7.7, 1.2 Hz, 1H), 6.92 (dt, J=11.9,2.0 Hz, 1H), 6.82 (tdd, J=8.1, 2.6, 0.9 Hz, 1H), 6.47 (d, J=16.0 Hz,1H), 6.28 (dd, J=16.0, 5.4 Hz, 1H), 5.12 (d, J=5.2 Hz, 1H), 4.01-3.92(m, 1H), 3.82 (s, 3H), 3.80-3.78 (m, 1H), 3.74 (s, 3H), 2.63-2.55 (m,1H), 2.27 (dt, J=18.0, 3.5 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.1, 167.8, 137.4, 133.4, 129.6,126.0, 119.4, 113.9, 112.1, 80.0, 66.4, 63.4, 55.3, 52.3, 41.5 for ketoform; 171.0, 170.7, 159.8, 138.1, 132.9, 129.6, 128.7, 119.3, 113.6,111.9, 99.0, 70.7, 58.6, 51.6, 29.0 for enol form.

HRMS (ESI) calculated for C₁₆H₁₈O₅ [M+Na]⁺: 313.1052. Found: 313.1049.

Chiral SFC (Chiralpak ID-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 3.1 min (major), 1.7 min (minor).

Yellow oil. (40.9 mg, 70% yield, 92:8 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.48-7.37 (m, 1H), 7.25-7.20 (m, 1H),7.02 (d, J=16.0 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H),6.20 (dd, J=16.1, 6.7 Hz, 1H), 4.58 (dd, J=10.5, 6.3 Hz, 1H), 4.38 (ddd,J=11.6, 7.3, 1.7 Hz, 1H), 3.89-3.85 (m, 1H), 3.84 (s, 3H), 3.74 (s, 3H),3.49 (d, J=10.2 Hz, 1H), 2.76-2.65 (m, 1H), 2.50 (dt, J=14.7, 2.6 Hz,1H) for keto form; 12.22 (s, 1H), 7.48-7.37 (m, 1H), 7.25-7.20 (m, 1H),6.92 (t, J=7.4 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 6.82 (d, J=16.1 Hz, 1H),6.29 (dd, J=16.1, 5.5 Hz, 1H), 5.12 (d, J=5.5 Hz, 1H), 4.06-3.95 (m,1H), 3.84 (s, 3H), 3.83-3.78 (m, 1H), 3.74 (s, 3H), 2.63-2.54 (m, 1H),2.27 (dt, J=18.0, 3.5 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.5, 171.2, 170.7, 168.0,157.2, 157.0, 129.5, 129.0, 129.0, 128.9, 128.2, 127.5, 127.4, 127.2,126.4, 125.9, 125.1, 120.8, 120.7, 111.0, 111.0, 99.5, 80.7, 71.3, 66.4,63.8, 58.7, 55.6, 52.3, 51.6, 41.6, 29.1.

HRMS (ESI) calculated for C16H1805[M+Na]⁺: 313.1052. Found: 313.1053.

Chiral SFC (Chiralpak IB-3, 2% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 4.4 min (major), 3.6 min (minor) and 4.9 min (major), 6.5 min(minor) (keto/enol forms were not assigned).

White solid. (46.3 mg, 84% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.31-7.24 (m, 2H), 7.13 (d, J=7.7 Hz,2H), 6.68 (d, J=15.9 Hz, 1H), 6.12 (dd, J=15.9, 6.7 Hz, 1H), 4.57 (dd,J=10.8, 6.8 Hz, 1H), 4.37 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.90-3.83 (m,1H), 3.73 (s, 3H), 3.47 (d, J=10.1 Hz, 1H), 2.75-2.65 (m, 1H), 2.53-2.46(m, 1H), 2.34 (s, 3H) for keto form; 12.21 (s, 1H), 7.31-7.24 (m, 2H),7.13 (d, J=7.7 Hz, 2H), 6.46 (d, J=16.0 Hz, 1H), 6.24 (dd, J=16.0, 5.4Hz, 1H), 5.11 (d, J=5.5 Hz 1H), 3.99-3.91 (m, 1H), 3.82-3.77 (m, 1H),3.73 (s, 3H), 2.63-2.54 (m, 1H), 2.34 (s, 3H), 2.26 (dt, J=18.0, 3.7 Hz,1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 171.2, 170.8, 168.0,138.4, 137.9, 133.9, 133.7, 133.3, 133.1, 129.5, 129.4, 127.5, 126.8,126.7, 124.7, 99.3, 80.3, 70.9, 66.5, 63.7, 58.7, 52.4, 51.7, 41.6,29.1, 21.4, 21.4.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1103.

Chiral SFC (Chiralpak IB-3, 2% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.3 min (major), 2.0 min (minor) and 2.6 min (major), 2.9 min(minor) (keto/enol forms were not assigned).

White solid. (39.2 mg, 71% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.24-7.16 (m, 3H), 7.12-7.04 (m, 1H),6.68 (d, J=15.9 Hz, 1H), 6.15 (dd, J=15.9, 6.7 Hz, 1H), 4.57 (ddd,J=10.2, 6.7, 1.1 Hz, 1H), 4.37 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.86 (td,J=12.0, 2.9 Hz, 1H), 3.74 (s, 3H), 3.47 (d, J=10.2 Hz, 1H), 2.74-2.66(m, 1H), 2.54-2.48 (m, 1H), 2.35 (s, 3H) for keto form; 12.21 (s, 1H),7.24-7.16 (m, 3H), 7.12-7.04 (m, 1H), 6.47 (d, J=16.0 Hz, 1H), 6.28 (dd,J=16.0, 5.4 Hz, 1H), 5.12 (d, J=5.3 Hz, 1H), 4.02-3.91 (m, 1H),3.83-3.78 (m, 1H), 3.74 (s, 3H), 2.64-2.54 (m, 1H), 2.35 (s, 3H), 2.26(dt, J=18.0, 3.5 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.2, 171.0, 170.7, 167.9,138.2, 138.2, 136.5, 135.9, 133.7, 133.1, 129.1, 128.6, 128.5, 128.5,128.2, 127.5, 127.4, 125.5, 123.9, 123.8, 99.1, 80.1, 70.7, 66.3, 63.5,58.5, 52.3, 51.6, 41.5, 29.0, 21.4, 21.4.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1103.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 3.9 min (major), 2.6 min (minor) and 6.5 min (major), 16.0 min(minor) (keto/enol forms were not assigned).

Yellow oil. (44.4 mg, 81% yield, 96:4 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.42-7.38 (m, 1H), 7.20-7.10 (m, 3H),6.93 (d, J=15.8 Hz, 1H), 6.04 (dd, J=15.8, 6.7 Hz, 1H), 4.60 (dd,J=10.2, 6.7 Hz, 1H), 4.39 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.90-3.84 (m,1H), 3.75 (s, 3H), 3.49 (d, J=10.2 Hz, 1H), 2.76-2.66 (m, 1H), 2.54-2.48(m, 1H), 2.33 (s, 3H) for keto form; 12.21 (s, 1H), 7.44-7.42 (m, 1H),7.20-7.10 (m, 3H), 6.74 (d, J=15.8 Hz, 1H), 6.13 (dd, J=15.8, 5.6 Hz,1H), 5.12 (d, J=5.5 Hz, 1H), 4.04-3.96 (m, 1H), 3.84-3.80 (m, 1H), 3.75(s, 3H), 2.64-2.55 (m, 1H), 2.33 (s, 3H), 2.29 (dt, J=18.0, 3.7 Hz, 1H)for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 171.1, 170.8, 168.0,136.1, 136.0, 135.6, 135.4, 131.8, 131.1, 130.4, 130.4, 130.0, 128.3,127.8, 127.4, 126.3, 126.3, 126.1, 126.0, 99.3, 80.4, 71.2, 66.5, 63.7,58.8, 52.4, 51.7, 41.6, 29.1, 19.9, 19.9.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1101.

Chiral SFC (Chiralpak IC-3, 1.5% MeOH in CO₂, flow rate=2.5 mL/min,λ=250 nm): 5.6 min (major), 3.7 min (minor) and 6.5 min (major), 7.3 min(minor) (keto/enol forms were not assigned).

White solid. (40.2 mg, 59% yield, 94:6 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.48-7.41 (m, 2H), 7.27-7.21 (m, 2H),6.66 (d, J=15.9 Hz, 1H), 6.16 (dd, J=15.9, 6.5 Hz, 1H), 4.57 (dd,J=10.7, 6.1 Hz, 1H), 4.38 (ddd, J=11.7, 7.4, 1.7 Hz, 1H), 3.90-3.84 (m,1H), 3.74 (s, 3H), 3.46 (d, J=10.3 Hz, 1H), 2.76-2.66 (m, 1H), 2.51(ddd, J=14.6, 2.6, 1.6 Hz, 1H) for keto form; 12.20 (s, 1H), 7.48-7.41(m, 2H), 7.27-7.21 (m, 2H), 6.45 (d, J=16.0 Hz, 1H), 6.28 (dd, J=16.0,5.3 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 3.99-3.91 (m, 1H), 3.84-3.78 (m,1H), 3.74 (s, 3H), 2.64-2.54 (m, 1H), 2.28 (dt, J=18.0, 3.6 Hz, 1H) forenol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.1, 171.0, 170.9, 167.9,135.7, 135.0, 132.4, 131.9, 131.8, 131.8, 129.4, 128.4, 128.3, 126.6,122.4, 121.7, 99.0, 80.0, 70.8, 66.5, 63.5, 58.9, 52.4, 51.8, 41.6,29.1.

HRMS (ESI) calculated for C₁₅H₁₅BrO₄ [M+Na]⁺: 361.0051. Found: 361.0047.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 5.7 min (major), 5.2 min (minor).

White solid. (37.5 mg, 55% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.57-7.50 (m, 1H), 7.42-7.35 (m, 1H),7.29 (t, J=8.3 Hz, 1H), 7.19 (td, J=7.8, 1.7 Hz, 1H), 6.65 (d, J=15.9Hz, 1H), 6.17 (dd, J=15.9, 6.4 Hz, 1H), 4.58 (ddd, J=10.3, 6.4, 1.2 Hz,1H), 4.38 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.89-3.83 (m, 1H), 3.76 (s,3H), 3.45 (d, J=10.3 Hz, 1H), 2.76-2.65 (m, 1H), 2.54-2.48 (m, 1H) forketo form; 12.20 (s, 1H), 7.57-7.50 (m, 1H), 7.42-7.35 (m, 1H), 7.29 (t,J=8.3 Hz, 1H), 7.19 (td, J=7.8, 1.7 Hz, 1H), 6.44 (d, J=16.0 Hz, 1H),6.29 (dd, J=16.0, 5.3 Hz, 1H), 5.11 (d, J=5.2 Hz, 1H), 3.97-3.91 (m,1H), 3.83-3.79 (m, 1H), 3.75 (s, 3H), 2.63-2.54 (m, 1H), 2.27 (dt,J=18.0, 3.6 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.0, 171.0, 171.0, 167.9,138.9, 138.2, 132.0, 131.5, 131.3, 130.8, 130.3, 130.2, 130.2, 129.7,129.6, 127.4, 125.6, 125.4, 123.0, 122.9, 99.0, 79.8, 70.7, 66.5, 63.4,58.9, 52.5, 51.8, 41.6, 29.1.

HRMS (ESI) calculated for C₁₅H₁₅BrO₄ [M+Na]⁺: 361.0051. Found: 361.0044.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 4.9 min (major), 4.1 min (minor).

White solid. (40.1 mg, 68% yield, 96:4 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.38 (s, 1H), 7.29-7.20 (m, 3H), 6.68 (d,J=15.9 Hz, 1H), 6.19 (dd, J=15.9, 6.4 Hz, 1H), 4.59 (ddd, J=10.3, 6.4,1.2 Hz, 1H), 4.40 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.91-3.85 (m, 1H),3.77 (s, 3H), 3.47 (d, J=10.3 Hz, 1H), 2.77-2.67 (m, 1H), 2.53 (ddd,J=14.7, 2.9, 1.6 Hz, 1H) for keto form; 12.22 (s, 1H), 7.40 (s, 1H),7.29-7.20 (m, 3H), 6.47 (d, J=16.0 Hz, 1H), 6.32 (dd, J=16.0, 5.3 Hz,1H), 5.13 (d, J=5.2 Hz, 1H), 4.00-3.93 (m, 1H), 3.85-3.81 (m, 1H), 3.77(s, 3H), 2.65-2.56 (m, 1H), 2.29 (dt, J=18.0, 3.6 Hz, 2H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.0, 171.0, 171.0, 167.9,138.7, 137.9, 134.8, 134.7, 132.2, 131.6, 130.2, 130.0, 129.9, 128.4,127.9, 127.3, 126.8, 126.7, 125.1, 125.0, 99.0, 79.8, 70.8, 66.5, 63.4,58.9, 52.5, 51.8, 41.6, 29.1.

HRMS (ESI) calculated for C₁₅H₁₅ClO₄[M+Na]⁺: 317.0557. Found: 317.0549.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 4.0 min (major), 3.3 min (minor).

Yellow oil. (34.0 mg, 58% yield, 97:3 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.50-7.47 (m, 1H), 7.35 (d, J=7.0 Hz,1H), 7.25-7.16 (m, 2H), 7.09 (d, J=15.9 Hz, 1H), 6.15 (dd, J=15.9, 6.4Hz, 1H), 4.62 (dd, J=10.3, 6.4 Hz, 1H), 4.39 (dd, J=11.4, 7.1 Hz, 1H),3.91-3.85 (m, 1H), 3.77 (s, 3H), 3.48 (d, J=10.4 Hz, 1H), 2.77-2.67 (m,1H), 2.54-2.48 (m, 1H) for keto form; 12.22 (s, 1H), 7.54-7.50 (m, 1H),7.35 (d, J=7.0 Hz, 1H), 7.25-7.16 (m, 2H), 6.91 (dd, J=16.0, 1.5 Hz,1H), 6.22 (dd, J=15.9, 5.6 Hz, 1H), 5.14 (d, J=5.5 Hz, 1H), 4.03-3.96(m, 1H), 3.85-3.81 (m, 1H), 3.76 (s, 3H), 2.63-2.54 (m, 1H), 2.30 (dt,J=17.9, 3.7 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.1, 171.0, 170.9, 167.9,135.2, 134.4, 133.6, 133.3, 131.4, 129.9, 129.8, 129.5, 129.4, 128.9,128.8, 127.2, 127.1, 127.0, 99.0, 79.9, 71.1, 66.6, 63.6, 59.0, 52.5,51.7, 41.6, 29.1.

HRMS (ESI) calculated for C₁₅H₁₅ClO₄ [M+Na]⁺: 317.0557. Found: 317.0554.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.7 min (major), 2.4 min (minor).

Yellow solid. (48.1 mg, 77% yield, 94:6 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.87-7.72 (m, 4H), 7.58 (dd, J=8.6, 1.7Hz, 1H), 7.51-7.41 (m, 2H), 6.88 (d, J=15.9 Hz, 1H), 6.30 (dd, J=15.9,6.6 Hz, 1H), 4.65 (ddd, J=10.2, 6.6, 1.1 Hz, 1H), 4.40 (ddd, J=11.6,7.3, 1.7 Hz, 1H), 3.92-3.86 (m, 1H), 3.75 (s, 3H), 3.53 (d, J=10.2 Hz,1H), 2.77-2.68 (m, 1H), 2.56-2.48 (m, 1H) for keto form; 12.25 (s, 1H),7.87-7.72 (m, 4H), 7.62 (dd, J=8.6, 1.8 Hz, 1H), 7.51-7.41 (m, 2H), 6.68(d, J=16.0 Hz, 1H), 6.42 (dd, J=15.9, 5.4 Hz, 1H), 5.18 (d, J=5.3 Hz,1H), 4.01 (ddd, J=11.7, 9.6, 4.3 Hz, 1H), 3.86-3.81 (m, 1H), 3.76 (s,3H), 2.66-2.56 (m, 1H), 2.30 (dt, J=18.0, 3.6 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 171.1, 170.9, 168.0,134.2, 133.8, 133.7, 133.6, 133.5, 133.4, 133.2, 128.9, 128.4, 128.4,128.2, 128.1, 127.8, 127.8, 127.4, 126.9, 126.6, 126.5, 126.4, 126.1,126.1, 123.7, 123.6, 99.2, 80.3, 71.0, 66.5, 63.6, 58.8, 52.4, 51.8,41.7, 29.1.

HRMS (ESI) calculated for C19H₁₈O₄ [M+Na]⁺: 333.1103. Found: 333.1101.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 10.6 min (major), 9.3 min (minor).

Yellow solid. (49.4 mg, 80% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 8.05 (d, J=8.0 Hz, 1H), 7.88-7.84 (m,1H), 7.80 (t, J=8.3 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.55-7.42 (m, 4H),6.20 (dd, J=15.6, 6.6 Hz, 1H), 4.72 (ddd, J=10.4, 6.6, 1.2 Hz, 1H), 4.43(ddd, J=11.6, 7.3, 1.6 Hz, 1H), 3.94-3.89 (m, 1H), 3.76 (s, 3H), 3.56(d, J=10.3 Hz, 1H), 2.79-2.70 (m, 1H), 2.54 (ddd, J=14.7, 2.8, 1.6 Hz,1H) for keto form; 12.26 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88-7.84 (m,1H), 7.80 (t, J=8.3 Hz, 1H), 7.60 (d, J=7.1 Hz, 1H), 7.55-7.42 (m, 3H),7.30 (d, J=15.7 Hz, 1H), 6.30 (dd, J=15.7, 5.5 Hz, 1H), 5.22 (d, J=5.4Hz, 1H), 4.13-4.04 (m, 1H), 3.89-3.85 (m, 1H), 3.79 (s, 3H), 2.68-2.59(m, 1H), 2.34 (dt, J=18.0, 3.6 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.2, 171.2, 170.9, 168.1,134.7, 134.0, 133.7, 133.7, 131.8, 131.3, 131.3, 131.2, 130.4, 129.1,128.7, 128.2, 126.4, 126.2, 126.1, 125.9, 125.7, 125.7, 124.3, 124.1,123.8, 99.3, 80.4, 71.3, 66.6, 63.7, 59.0, 52.4, 51.7, 41.6, 29.2.

HRMS (ESI) calculated for C₁₉H₁₈O₄ [M+Na]⁺: 333.1103. Found: 333.1101.

Chiral SFC (Chiralpak ID-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.6 min (major), 2.0 min (minor).

White solid. (47.5 mg, 87% yield, 97:3 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.33 (t, J=7.6 Hz, 2H), 7.27-7.21 (m,3H), 6.55 (s, 1H), 4.48 (d, J=10.3 Hz, 1H), 4.37 (ddd, J=11.5, 7.4, 1.6Hz, 1H), 3.87 (td, J=11.8, 2.8 Hz, 1H), 3.72 (s, 3H), 3.67 (d, J=10.7Hz, 1H), 2.74-2.62 (m, 1H), 2.50 (ddd, J=14.9, 2.8, 1.5 Hz, 1H), 1.95(s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.7, 167.9, 136.8, 134.3, 130.1,129.1, 128.3, 127.2, 85.7, 66.4, 61.9, 52.4, 41.5, 13.0.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1104.

Chiral SFC (Chiralpak ID-3, 1% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 4.0 min (major), 3.3 min (minor).

White foam solid. (49.7 mg, 55% yield, 87:13 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.99 (dd, J=8.3, 3.6 Hz, 1H), 7.77 (dd,J=8.4, 6.2 Hz, 2H), 7.68 (d, J=7.9 Hz, 1H), 7.60 (d, J=6.0 Hz, 1H),7.36-7.31 (m, 1H), 7.29-7.25 (m, 1H), 7.22 (d, J=8.2 Hz, 2H), 6.79 (d,J=16.1 Hz, 1H), 6.23 (dd, J=16.1, 6.6 Hz, 1H), 4.58 (dd, J=10.2, 6.6 Hz,1H), 4.39 (ddd, J=11.6, 7.3, 1.7 Hz, 1H), 3.87 (td, J=11.9, 2.8 Hz, 1H),3.75 (s, 3H), 3.50 (d, J=10.2 Hz, 1H), 2.75-2.67 (m, 1H 2.52 (dq,J=14.6, 1.7 Hz, 1H), 2.34 (s, 3H) for keto form; 12.21 (s, 1H), 7.99(dd, J=8.3, 3.6 Hz, 1H), 7.77 (dd, J=8.4, 6.2 Hz, 2H), 7.71 (d, J=7.8Hz, 1H), 7.60 (d, J=6.0 Hz, 1H), 7.36-7.31 (m, 1H), 7.29-7.25 (m, 1H),7.22 (d, J=8.2 Hz, 2H), 6.58 (d, J=16.2 Hz, 1H), 6.36 (dd, J=16.2, 5.4Hz, 1H), 5.13 (d, J=5.5 Hz, 1H), 4.02-3.94 (m, 1H), 3.84-3.79 (m, 1H),3.75 (s, 3H), 2.63-2.55 (m, 1H), 2.34 (s, 3H), 2.30 (dt, J=18.0, 3.7 Hz,1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.1, 171.1, 170.9, 168.0,145.3, 145.2, 135.6, 135.6, 135.3, 135.2, 130.1, 130.1, 129.8, 129.1,128.9, 127.0, 126.9, 125.2, 125.1, 125.0, 124.5, 124.4, 123.8, 123.7,123.6, 120.5, 120.4, 120.0, 119.3, 113.9, 113.9, 99.0, 80.4, 71.2, 66.5,63.6, 58.9, 52.5, 51.8, 41.7, 29.1, 21.7.

HRMS (ESI) calculated for C₂₄H₂₃NO₆S [M+Na]⁺: 476.1144. Found: 476.1138.

Chiral SFC (Chiralpak IC-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 5.4 min (minor), 5.9 min (major) and 10.5 min (major), 12.1 min(minor) (keto/enol forms were not assigned).

Yellow oil. (36.5 mg, 69% yield, 88:12 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.19 (d, J=5.0 Hz, 1H), 7.02-6.93 (m,2H), 6.83 (d, J=15.7 Hz, 1H), 6.00 (dd, J=15.7, 6.6 Hz, 1H), 4.54 (ddd,J=10.3, 6.6, 1.2 Hz, 1H), 4.36 (ddd, J=11.6, 7.2, 1.7 Hz, 1H), 3.84 (td,J=11.8, 2.8 Hz, 1H), 3.75 (s, 3H), 3.46 (d, J=10.2 Hz, 1H), 2.74-2.65(m, 1H), 2.49 (ddd, J=14.7, 2.8, 1.7 Hz, 1H) for keto form; 12.20 (s,1H), 7.18-7.15 (m, 1H), 7.02-6.93 (m, 2H), 6.62 (d, J=15.8 Hz, 1H), 6.13(dd, J=15.8, 5.4 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 3.99-3.91 (m, 1H),3.81-3.78 (m, 1H), 3.75 (s, 3H), 2.63-2.54 (m, 1H), 2.25 (ddd, J=18.0,4.3, 2.8 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.2, 171.0, 170.9, 167.9,141.9, 141.0, 128.2, 127.6, 127.5, 127.1, 126.8, 126.3, 126.3, 125.4,125.1, 124.7, 99.0, 79.9, 70.6, 66.4, 63.5, 58.7, 52.4, 51.8, 41.6,29.0.

HRMS (ESI) calculated for C₁₃H₁₄O₄ [M+Na]⁺: 289.0510. Found: 289.0507.

Chiral SFC (Chiralpak IG-3, 30% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.1 min (minor), 2.4 min (major).

Yellow solid. (28.8 mg, 50% yield, 91:9 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.39 (d, J=7.3 Hz, 2H), 7.32 (t, J=7.6Hz, 2H), 7.26-7.21 (m, 1H), 6.73 (dd, J=15.6, 10.5 Hz, 1H), 6.60 (d,J=15.6 Hz, 1H), 6.50 (dd, J=15.2, 10.4 Hz, 1H), 5.77 (dd, J=15.2, 6.7Hz, 1H), 4.51 (ddd, J=10.2, 6.6, 1.1 Hz, 1H), 4.35 (ddd, J=11.6, 7.3,1.7 Hz, 1H), 3.84 (td, J=11.9, 2.9 Hz, 1H), 3.76 (s, 3H), 3.43 (d,J=10.2 Hz, 1H), 2.73-2.63 (m, 1H), 2.49 (ddd, J=14.6, 2.9, 1.7 Hz, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.3, 168.0, 136.9, 134.8, 134.0,129.3, 128.8, 128.1, 127.6, 126.7, 79.9, 66.5, 63.6, 52.4, 41.6.

HRMS (ESI) calculated for C₁₇H₁₈O₄ [M+Na]⁺: 309.1103. Found: 309.1100.

Chiral SFC (Chiralpak IG-3, 30% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 4.0 min (minor), 5.3 min (major).

White solid. (26.4 mg, 50% yield, 91:9 e.r., reaction for 20 h at −30°C.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.32 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 4.85 (d, J=10.4 Hz, 1H), 4.40 (ddd, J=11.6, 7.5, 1.5 Hz, 1H),3.91 (td, J=12.2, 2.7 Hz, 1H), 3.80 (s, 3H), 3.67 (d, J=11.1 Hz, 1H),3.61 (s, 3H), 2.84-2.72 (m, 1H), 2.58-2.50 (m, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 201.6, 167.9, 160.0, 130.8, 128.3,114.2, 81.7, 66.8, 65.0, 55.4, 52.2, 41.7.

HRMS (ESI) calculated for C₁₄H₁₆O₅ [M+Na]⁺: 287.0895. Found: 287.0897.

Chiral SFC (Chiralpak IG-3, 20% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.1 min (major), 1.7 min (minor).

White solid. (29.4 mg, 50% yield, 89:11 e.r., reaction for 4 h at −30°C.)

¹H NMR (500 MHz, CDCl₃): δ ppm 6.95-6.88 (m, 2H), 6.86-6.78 (m, 1H),4.86 (d, J=10.4 Hz, 1H), 4.41 (ddd, J=11.6, 7.4, 1.5 Hz, 1H), 3.95-3.90(m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 3.67 (d, J=10.4 Hz, 1H), 3.62 (s,3H), 2.84-2.72 (m, 1H), 2.54 (ddd, J=14.6, 2.8, 1.5 Hz, 1H) for ketoform; 12.25 (s, 1H), 6.95-6.88 (m, 2H), 6.86-6.78 (m, 1H), 5.45 (s, 1H),3.89 (s, 3H), 3.87 (s, 3H), 3.74-3.70 (m, 2H), 3.59 (s, 3H), 2.64-2.58(m, 1H), 2.34 (dt, J=18.0, 4.0 Hz, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.4, 171.0, 170.9, 167.8,149.3, 149.1, 148.9, 148.8, 133.5, 131.1, 120.6, 119.3, 111.5, 111.0,110.3, 109.7, 99.3, 81.7, 73.1, 66.7, 64.9, 58.5, 55.9, 55.9, 52.1,51.5, 41.5, 29.0.

HRMS (ESI) calculated for C₁₅H₁₈O₆ [M+Na]⁺: 317.1001. Found: 317.1002.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.9 min (major), 2.6 min (minor).

Colorless oil. (36.3 mg, 83% yield, 91:9 e.r., reaction for 45 h at −30°C.)

¹H NMR (500 MHz, CDCl₃): δ ppm 6.61 (s, 2H), 4.98-4.79 (m, 1H), 4.43(ddd, J=11.6, 7.4, 1.5 Hz, 1H), 3.94-3.89 (m, 1H), 3.86 (s, 6H), 3.83(s, 3H), 3.69-3.64 (m, 4H), 2.84-2.73 (m, 1H), 2.58-2.53 (m, 1H) forketo form; 12.26 (s, 1H), 6.52 (s, 2H), 5.42 (s, 1H), 3.85 (s, 6H), 3.84(s, 3H), 3.79-3.70 (m, 2H), 3.61 (s, 3H), 2.62-2.58 (m, 1H), 2.44-2.37(m, 1H) for enol form.

¹³C NMR (125 MHz, CDCl₃): δ ppm (keto+enol) 201.3, 171.2, 171.1, 167.9,153.5, 153.2, 138.4, 137.9, 136.8, 134.3, 105.6, 103.8, 102.5, 99.3,81.9, 73.8, 66.8, 65.0, 61.0, 59.3, 56.3, 56.3, 52.3, 51.7, 41.6, 29.2.

HRMS (ESI) calculated for C₁₆H₂₀O₇ [M+Na]⁺: 347.1107. Found: 347.1110.

Chiral SFC (Chiralpak IC-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.8 min (major), 3.7 min (minor) and 3.1 min (major), 4.2 min(minor) (keto/enol forms were not assigned).

White solid (35.5 mg, 65% yield, >20:1 dr, 96:4 er).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.36 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.5Hz, 2H), 7.29-7.23 (m, 1H), 6.71 (d, J=15.9 Hz, 1H), 6.01 (dd, J=15.9,6.1 Hz, 1H), 4.82 (dd, J=6.1, 1.2 Hz, 1H), 4.35 (ddd, J=11.6, 7.4, 2.5Hz, 1H), 3.90 (td, J=11.4, 3.7 Hz, 1H), 3.79 (s, 3H), 2.81 (ddd, J=15.2,11.4, 7.4 Hz, 1H), 2.44 (ddd, J=15.2, 3.7, 2.4 Hz, 1H), 1.41 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 205.6, 171.2, 136.3, 134.0, 128.7,128.3, 126.8, 123.2, 81.7, 66.1, 63.3, 52.6, 38.2, 15.1.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1108.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 2.9 min (major), 5.6 min (minor).

The stereochemistry of the product was determined by NOESY experiments(data not shown).

CDC Reaction of Unsuccessful Substrates

Under optimized conditions, we examined a few more substrates 1u-1y (asshown above). We observed that reaction of 1u, 1v and 1y gave traceamount of desired products after 24 hours even upon warming to roomtemperature, and starting materials were isolated in >85% yield. Thereaction of allyl ether 1w provided overoxidized side products, but thedesired product was not obtained. Furthermore, we attempted toenantioselectivity access tetrahydrofurans using our optimized reactionconditions; however, 1x did not provide the desired product uponextensive reaction testing. In the reaction of 1x, cyclic acetalcompounds S2x were obtained (see below).

Pale yellow solid. (38.4 mg, 74% yield, spectra data for the majorcompound was attached.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.46-7.40 (m, 2H), 7.38-7.29 (m, 3H),6.89 (d, J=16.0 Hz, 1H), 6.23 (dd, J=16.0, 6.3 Hz, 1H), 6.03 (d, J=6.2Hz, 1H), 4.94 (t, J=1.4 Hz, 1H), 4.73 (dd, J=13.6, 1.2 Hz, 1H), 4.59(dd, J=13.5, 1.5 Hz, 1H), 4.18 (qd, J=7.1, 1.1 Hz, 2H), 1.27 (t, J=7.1Hz, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 165.3, 163.1, 137.5, 135.1, 129.2,128.8, 127.4, 122.2, 109.8, 87.2, 69.5, 59.9, 14.5.

LRMS (ESI) calculated for C₁₅H₁₆O₄ [M+H]⁺: 261.1. Found: 261.1.

Synthesis of Enol Acetate 3

To a solution of cinnamyl bromide (0.74 mL, 5.0 mmol) and 3-butyn-1-ol(0.45 mL, 6.0 mmol) in THF was added sodium hydride (60% dispersion inmineral oil, 300 mg, 7.5 mmol) at 0° C. The solution was stirred for 3 hat ambient temperature and then saturated NH₄Cl solution was added toquench the reaction, followed by addition of ethyl acetate. The aqueouslayer was extracted with ethyl acetate, dried and concentrated in vacuo.The crude was purified by silica gel column chromatography with ethylacetate/hexane (1:10) to give the homopropargylic cinnamyl ether ascolorless oil (649.6 mg, 70% yield). (See Gudla, V.; Balamurugan, R. J.Org. Chem. 2011, 76, 9919).

To a mixture of [Ru(p-cymene)Cl₂]₂ (12.2 mg, 0.02 mmol),tri(2-furyl)phosphine (9.3 mg, 0.04 mmol), Na₂CO₃ (106.0 mg, 1.0 mmol),and the homopropargylic cinnamyl ether (37.3 mg, 0.2 mmol) in toluene(4.0 mL) was added acetic acid (0.57 mL, 10 mmol). The solution wasstirred at 80° C. for 15 min and then a solution of the homopropargyliccinnamyl ether (335.3 mg, 1.8 mmol) in 1.0 mL toluene was added. Theresulting solution was stirred at 80° C. for 20 h. The crude mixture wascooled to room temperature and concentrated in vacuo. The crude waspurified by silica gel column chromatography with ethyl acetate/hexane(1:10) to give the enol acetate 3 as colorless oil (286.8 mg, 77%yield). (See Jung, H. H.; Floreancig, P. E. Tetrahedron 2009, 65, 1083).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.39 (d, J=7.5 Hz, 2H), 7.32 (t, J=7.6Hz, 2H), 7.27-7.20 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.28 (dt, J=16.0,6.0 Hz, 1H), 4.86-4.75 (m, 2H), 4.16 (dd, J=6.0, 1.5 Hz, 2H), 3.62 (t,J=6.6 Hz, 2H), 2.55 (t, J=6.6 Hz, 2H), 2.13 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 169.3, 153.6, 136.8, 132.6, 128.7,127.8, 126.6, 126.1, 103.1, 71.6, 67.1, 34.1, 21.2.

HRMS (ESI) calculated for C1411803 [M+Na]⁺: 269.1154. Found: 269.1152.

CDC Reaction of Enol Acetate 3

To an oven dried 20 mL reaction vial equipped with a magnetic stir barunder N₂ was added Na₂HPO₄ (56.8 mg, 0.4 mmol), 250 mg of 4 Å molecularsieve (powder), 1.0 mL of L3.Cu(OTf)₂ (0.02 M in CH₂Cl₂), and 4.0 mL ofCH₂Cl₂. The solution then was stirred for 1 h. The enol acetate 3 wasdissolved in 1.0 mL of CH₂Cl₂ and was added, and the solution stirred atambient temperature for 30 minutes. The reaction was then cooled to −70°C., and DDQ (59.0 mg, 0.26 mmol) dissolved in 4.0 mL of DCM was addedover 1 h by syringe pump. The reaction was stirred for 12 h at −70° C.,and then 1.0 mL of Et₃N was added to quench the reaction. The solutionwas filtered over a pad of silica (4 cm) with ethyl acetate andconcentrated under reduced pressure. The crude was purified by silicagel column chromatography with ethyl acetate/hexane (1:4) to give thetetrahydropyran-4-ones 4 (27.5 mg, 68% yield, 50:50 e.r.).

CDC Reaction of Cinnamylmethyl Ether with Methyl 2-Acetoacetate

To an oven dried 20 mL reaction vial equipped with a magnetic stir barunder N₂ was added Na₂HPO₄ (56.8 mg, 0.4 mmol), 250 mg of 4 Å molecularsieve (powder), 1.0 mL of L3.Cu(OTf)₂ (0.02 M in CH₂Cl₂), and 4.0 mL ofCH₂Cl₂. The solution then was stirred for 1 h. The cinnamylmethyl etherand methyl 2-acetoacetate were dissolved in 1.0 mL of CH₂Cl₂ and wasadded, and the solution stirred at ambient temperature for 30 minutes.The reaction was then cooled to −70° C., and DDQ (59.0 mg, 0.26 mmol)dissolved in 4.0 mL of DCM was added over 1 h by syringe pump. Thereaction was stirred for 12 h at −70° C., and then 1.0 mL of Et₃N wasadded to quench the reaction. The solution was filtered over a pad ofsilica (4 cm) with ethyl acetate and concentrated under reduced pressure(During concentration of solvents, the desired coupling product wasconverted to the conjugated enones). The crude was purified by silicagel column chromatography with ethyl acetate/hexane (1:5) to give theconjugated enones (35.9 mg, 78% yield, E/Z=2.7:1). (See Paquette, L. A.;Kern, B. E.; Mendez-Andino, J. Tetrahedron. Lett. 1999, 40, 4129).

5. Transformation of Tetrahydropyran-4-One 2a

To a 5 mL reaction vial equipped with a magnetic stir bar was added the2a (26.0 mg, 0.1 mmol, 95:5 e.r.), 0.5 mL of DMF, and 20 μL of H₂O. Thesolution then was stirred for 5 h at 130° C. The crude was purified bysilica gel column chromatography with ethyl acetate/hexane (1:4) to givethe tetrahydropyran-4-one 4 as white solid (15.5 mg, 77% yield, 95:5e.r.). (See Reddy, B. V. S.; Anjum, S. R.; Sridhar, B. RSC Adv. 2016, 6,75133).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.29-7.24 (m, 2H), 7.23-7.17 (m, 2H),7.16-7.10 (m, 1H), 6.52 (d, J=16.0 Hz, 1H), 6.10 (dd, J=16.0, 5.9 Hz,1H), 4.35-4.13 (m, 2H), 3.66 (td, J=11.8, 3.0 Hz, 1H), 2.57-2.48 (m,1H), 2.47-2.36 (m, 2H), 2.31-2.20 (m, 1H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 206.3, 136.3, 131.8, 128.7, 128.2,128.1, 126.7, 78.3, 66.4, 48.3, 42.3.

Chiral SFC (Chiralpak IB-3, 3% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 3.1 min (major), 2.8 min (minor).

To an oven dried 5 mL reaction vial equipped with a magnetic stir barwas added the 2a (26.0 mg, 0.1 mmol, 95:5 e.r.), 4.8 mg of NaH (60% inoil, 0.12 mmol), and 1.0 mL of THF at 0° C. Methyl iodide (24.9 μL, 0.4mmol) was added to the solution. The solution was stirred for 1 h at 0°C. and then stirred for 16 h at ambient temperature additionally. Thesaturated NH₄C1 solution was added to quench the reaction, followed byaddition of ethyl acetate. The aqueous layer was extracted with ethylacetate, dried and concentrated in vacuo. The crude was purified bysilica gel column chromatography with ethyl acetate/hexane (1:4) to givethe methylated tetrahydropyran-4-one 7 as colorless oil (26.5 mg, 97%yield, 95:5 e.r., 13:1 d.r.). The stereochemistry of the product wasdetermined by NOESY experiments (data not shown).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.43-7.39 (m, 2H), 7.35-7.31 (m, 2H),7.29-7.25 (m, 1H), 6.63 (d, J=15.9 Hz, 1H), 6.49 (dd, J=15.9, 7.1 Hz,1H), 4.39 (ddd, J=11.4, 8.1, 1.1 Hz, 1H), 3.89 (dd, J=7.2, 1.0 Hz, 1H),3.85-3.78 (m, 1H), 3.73 (s, 3H), 3.22 (ddd, J=14.8, 12.7, 8.1 Hz, 1H),2.48 (ddd, J=14.8, 3.1, 1.1 Hz, 1H), 1.32 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 203.6, 170.5, 136.4, 134.0, 128.7,128.2, 126.9, 124.5, 86.8, 67.4, 62.2, 52.6, 41.1, 16.2.

HRMS (ESI) calculated for C₁₆H₁₈O₄ [M+Na]⁺: 297.1103. Found: 297.1110.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 3.4 min (major), 2.2 min (minor) for (2R,3S)-7 and 3.0 min (major),5.7 min (minor) for (2R,3R)-7.

To an oven dried 5 mL reaction vial equipped with a magnetic stir barwas added the corresponding tetrahydropyran-4-one (0.1 mmol, 95:5 e.r.),and 2.0 mL of THF at −70° C. The L-selectride (0.3 mL, 1.0 M in THF) wasslowly added to the solution. The solution was stirred for 3 h at −70°C. and then quenched with saturated NH₄C1 solution. The aqueous layerwas extracted with ethyl acetate, dried and concentrated in vacuo. Thecrude was purified by silica gel column chromatography with ethylacetate/hexane (1:2) to give the corresponding tetrahydropyran-4-ol.

White solid (16.8 mg, 64% yield, 95:5 e.r.)

¹H NMR (500 MHz, C₆D₆): δ ppm 7.24-7.20 (m, 2H), 7.09-7.04 (m, 2H),7.03-6.98 (m, 1H), 6.69 (d, J=15.9 Hz, 1H), 6.32 (dd, J=16.0, 6.8 Hz,1H), 4.73 (dd, J=10.1, 6.8 Hz, 1H), 4.14-3.97 (m, 2H), 3.67 (ddd,J=11.3, 4.8, 2.0 Hz, 1H), 3.47 (s, 1H), 3.15 (s, 3H), 2.54 (dd, J=10.3,2.2 Hz, 1H), 1.52-1.40 (m, 2H).

¹³C NMR (125 MHz, C₆D₆): δ ppm 174.0, 137.3, 132.1, 128.8, 128.7, 128.4,126.9, 74.2, 64.7, 62.2, 52.6, 51.3, 31.9.

HRMS (ESI) calculated for C₁₅H₁₈O₄ [M+Na]⁺: 285.1103. Found: 285.1108.

Chiral SFC (Chiralpak IC-3, 5% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 3.7 min (major), 3.4 min (minor).

Colorless oil (19.6 mg, 71% yield, 95:5 e.r.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.36-7.30 (m, 2H), 7.26 (dd, J=8.4, 6.8Hz, 2H), 7.21-7.17 (m, 1H), 6.52 (d, J=15.9 Hz, 1H), 6.37 (dd, J=15.9,7.1 Hz, 1H), 4.08 (ddd, J=11.7, 5.3, 2.1 Hz, 1H), 3.68 (s, 3H), 3.62 (d,J=7.6 Hz, 1H), 3.55 (td, J=11.8, 2.9 Hz, 1H), 3.49 (td, J=10.7, 4.8 Hz,1H), 3.02 (d, J=10.0 Hz, 1H), 2.20-2.08 (m, 1H), 1.93-1.81 (m, 1H), 1.30(s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 174.9, 136.9, 132.9, 128.7, 127.9,126.8, 125.9, 85.1, 75.4, 66.6, 52.5, 52.0, 32.6, 19.8.

HRMS (ESI) calculated for C₁₆H₂₀O₄[M+Na]⁺: 299.1259. Found: 299.1266.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 9.0 min (major), 7.7 min (minor).

To an oven dried 5 mL reaction vial equipped with a magnetic stir barwas added LiAlH₄ (19.0 mg, 0.5 mmol), and 3.0 mL of THF at 0° C. The 7(27.4 mg, 0.1 mmol, 95:5 e.r.) dissolved in 2.0 mL of THF was addedslowly and then the solution was stirred for 5 h at 0° C. The saturatedRochelle salt solution was added to quench the reaction, followed byaddition of ethyl acetate. The aqueous layer was extracted with ethylacetate, dried and concentrated in vacuo. The crude was purified bysilica gel column chromatography with ethyl acetate/hexane (1:1) to givethe dialcohol 10 as colorless oil (15.4 mg, 62% yield, 95:5 e.r.).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.39-7.35 (m, 2H), 7.31 (dd, J=8.5, 6.7Hz, 2H), 7.27-7.22 (m, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.17 (dd, J=15.9,6.3 Hz, 1H), 4.28 (d, J=11.1 Hz, 1H), 4.14 (ddd, J=11.7, 5.3, 1.5 Hz,1H), 3.73-3.63 (m, 3H), 3.59 (td, J=12.6, 2.6 Hz, 1H), 3.22 (s, 1H),2.58 (s, 1H), 2.14 (qd, J=12.8, 5.3 Hz, 1H), 1.91-1.85 (m, 1H), 1.18 (s,3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 136.7, 132.6, 128.7, 127.9, 126.6,124.9, 85.0, 77.3, 67.0, 65.0, 43.0, 32.5, 18.8.

HRMS (ESI) calculated for C₁₅H₂₀O₃[M+Na]⁺: 271.1310. Found: 271.1315.

Chiral SFC (Chiralpak IC-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 3.6 min (major), 4.4 min (minor).

To a 50 mL round bottom flask equipped with a magnetic stir bar wasadded 33.2 mg of Pd(TFA)₂ (0.1 mmol), and the 7 (274.3 mg, 1.0 mmol,93:7 e.r.). The flask was purged and filled with O₂ three times and thenan oxygen balloon was attached via a needle. 10 mL of DMSO bubbled withO₂ and the solution was stirred for 2 days at 80° C. Once 02 was vented,water was added to the solution, followed by addition of diethyl ether.The aqueous layer was extracted with diethyl ether, dried andconcentrated in vacuo. The crude was purified by silica gel columnchromatography with ethyl acetate/hexane (1:4) to give the cyclic enone11 as pale yellow solid (182.4 mg, 67% yield, 93:7 e.r.). (Startingmaterial 7 was hardly separated from product 11 by columnchromatography. Therefore, the reaction should be terminated after the 7is completely consumed. If the reaction does not give full conversion,the reaction can be performed again with crude mixture after workupprocess.)

¹H NMR (500 MHz, CDCl₃): δ ppm 7.48-7.42 (m, 3H), 7.38-7.34 (m, 2H),7.33-7.29 (m, 1H), 6.76 (d, J=15.9 Hz, 1H), 6.49 (dd, J=15.9, 8.1 Hz,1H), 5.58 (d, J=6.0 Hz, 1H), 4.70 (d, J=8.1 Hz, 1H), 3.72 (s, 3H), 1.39(s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 190.1, 169.8, 163.1, 137.0, 135.7,128.9, 128.8, 127.1, 121.9, 106.8, 86.7, 55.7, 52.8, 16.7.

HRMS (ESI) calculated for C₁₆H₁₆O₄[M+Na]⁺: 295.0946. Found: 295.0951.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 5.5 min (major), 2.5 min (minor).

A 10 mL flask was flushed with nitrogen and charged with Rh(cod)₂BF₄(4.1 mg, 0.01 mmol), 0.1 mL of degassed H₂O, and 2.0 mL of degasseddioxane. Phenylboronic acid (36.6 mg, 0.3 mmol) and the 11 (27.2 mg, 0.1mmol, 93:7 e.r.) were added to the solution. After being stirred at 100°C. for 12 h, the reaction mixture was passed through a pad of silica gelwith ethyl acetate and the solvent was removed under vacuum. The crudewas purified by silica gel column chromatography with ethylacetate/hexane (1:4) to give the tetrahydropyran-4-one 12 as colorlessoil (26.3 mg, 75% yield, 93:7 e.r.). The stereochemistry was assignedtrans configuration between C2-H and C6-H based on ¹H NMR data reportedin the literature. (See (a) Kumaraswamy, G.; Ramakrishna, G.; Naresh,P.; Jagadeesh, B.; Sridhar, B. J. Org. Chem. 2009, 74, 8468. (b)Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.; Maddaford, S.P. Org. Lett. 2001, 3, 2571).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.28-7.23 (m, 5H), 7.21-7.16 (m, 3H),7.15-7.10 (m, 2H), 6.38 (d, J=15.9 Hz, 1H), 6.28 (dd, J=15.9, 6.8 Hz,1H), 5.43 (dd, J=7.4, 3.1 Hz, 1H), 3.93 (d, J=6.8 Hz, 1H), 3.63 (s, 3H),3.35 (dd, J=15.4, 7.5 Hz, 1H), 2.99 (dd, J=15.4, 3.1 Hz, 1H), 1.13 (s,3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 204.3, 170.6, 139.4, 136.4, 133.7,128.9, 128.7, 128.4, 128.2, 127.3, 126.9, 124.4, 78.8, 74.8, 61.5, 52.7,42.5, 16.6.

HRMS (ESI) calculated for C₂₂H₂₂O₄ [M+Na]⁺: 373.1416. Found: 373.1430.

Chiral SFC (Chiralpak IC-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 1.7 min (major), 2.0 min (minor).

To an oven dried 10 mL vial equipped with a magnetic stir bar was added38.1 mg of CuI (0.2 mmol), THF (1.5 mL) and n-BuLi (0.16 mL, 2.5 M inHexanes) at 0° C. After being stirred for 20 min, the solution wascooled to −78° C. and then TMSCl (76 μl, 0.6 mmol) was added to thesolution. The 11 (27.2 mg, 0.1 mmol, 93:7 e.r.) dissolved in 1.5 mL ofTHF was added slowly. The solution was stirred for 2.5 h at −78° C. andthen quenched with saturated NH₄C1 solution. The aqueous layer wasextracted with ethyl acetate, dried and concentrated in vacuo. The crudewas purified by silica gel column chromatography with ethylacetate/hexane (1:4) to give the tetrahydropyran-4-one 13 as colorlessoil (25.0 mg, 76% yield, 93:7 e.r.). The trans stereochemistry of theproduct was determined by NOESY experiments (data not shown).

¹H NMR (500 MHz, CDCl₃): δ ppm 7.41 (d, J=7.3 Hz, 2H), 7.33 (t, J=7.5Hz, 2H), 7.28-7.23 (m, 1H), 6.62 (d, J=15.9 Hz, 1H), 6.46 (dd, J=15.9,7.2 Hz, 1H), 4.46-4.33 (m, 1H), 4.21 (d, J=7.1 Hz, 1H), 3.72 (s, 3H),3.18 (dd, J=14.7, 7.0 Hz, 1H), 2.44 (dd, J=14.7, 3.5 Hz, 1H), 1.78-1.65(m, 1H), 1.51-1.41 (m, 1H), 1.42-1.30 (m, 7H), 0.90 (td, J=5.6, 4.3, 1.7Hz, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 204.6, 170.6, 136.5, 133.7, 128.7,128.2, 126.9, 124.9, 78.7, 73.8, 61.5, 52.6, 44.3, 32.9, 27.7, 22.5,16.9, 14.1.

HRMS (ESI) calculated for C₂₀H₂₆O₄[M+Na]⁺: 353.1729. Found: 353.1744.

Chiral SFC (Chiralpak IG-3, 10% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 3.8 min (major), 1.8 min (minor).

To an oven dried 10 mL vial equipped with a magnetic stir bar was added2.2 mg of InCl₃ (0.01 mmol), the 11 (27.2 mg, 0.1 mmol, 93:7 e.r.), andCH₂Cl₂ (1 mL) at −78° C. Silyl enol ether (57.7 mg, 0.3 mmol) dissolvedin 0.5 mL of CH₂Cl₂ was added slowly and then the solution was stirredfor 4 h at −78° C. After warm up to 0° C., saturated KF solution wasadded and then stirred for 1 h at ambient temperature. The aqueous layerwas extracted with ethyl acetate, dried and concentrated in vacuo. Thecrude was purified by silica gel column chromatography with ethylacetate/hexane (1:4) to give the tetrahydropyran-4-one 14 as colorlessoil (36.5 mg, 93% yield, 93:7 e.r., 10:1 d.r.). The transstereochemistry of the product was determined by NOESY experiments (datanot shown).

¹H NMR (500 MHz, CDCl₃): δ ppm 8.01-7.89 (m, 2H), 7.61-7.55 (m, 1H),7.50-7.43 (m, 2H), 7.40-7.35 (m, 2H), 7.35-7.29 (m, 2H), 7.28-7.23 (m,1H), 6.56 (d, J=15.9 Hz, 1H), 6.41 (dd, J=15.8, 7.3 Hz, 1H), 5.07 (p,J=6.1, 5.5 Hz, 1H), 4.36 (d, J=7.2 Hz, 1H), 3.73 (s, 3H), 3.38 (dd,J=16.3, 5.6 Hz, 1H), 3.26 (ddd, J=15.4, 12.8, 7.2 Hz, 2H), 2.66 (dd,J=15.3, 4.9 Hz, 1H), 1.37 (s, 3H).

¹³C NMR (125 MHz, CDCl₃): δ ppm 204.2, 197.1, 170.5, 136.8, 136.3,134.3, 133.7, 128.9, 128.7, 128.3, 126.9, 124.2, 80.2, 70.4, 61.4, 52.7,43.6, 42.7, 17.2.

HRMS (ESI) calculated for C₂₄H₂₄O₅ [M+Na]⁺: 415.1521. Found: 415.1529.

Chiral SFC (Chiralpak IC-3, 5% MeOH in CO₂, flow rate=2.5 mL/min, λ=250nm): 8.8 min (major), 8.2 min (minor).

Stereochemical Models

The initial geometry of L3.Cu(II)(H₂O)₂ was based on the X-ray crystalstructure of [L1.Cu(H₂O)₂](SbF₆)₂ in the literature. (See Evans, D. A.;Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, 1635).Dihedral angles were fixed for optimization (as shown below). Geometryoptimization of L3.Cu(II) with 1a/DDQ intermediate (FIG. 3) wasperformed using the PM3 optimized structure of L3.Cu(II)(H₂O)₂ (FIG. 4).C1′-C2′ length was fixed to 2.2 Å.

Photoredox-Catalyzed CDC Reaction of 1a

To an over dried 25 mL round bottom flask equipped with a magnetic stirbar was charged with 1a (52.5 mg, 0.2 mmol), BrCCl₃ (39 μl, 0.4 mmol),150 mg 4 Å MS, Sc(OTf)₃ (9.8 mg, 0.02 mmol), and[Ir{dF(CF₃)ppy}₂(dtbbpy)]PF₆, (2.2 mg, 0.002 mmol), 2 mL of degassedCH₂Cl₂ was added to the flask, and the mixture was then irradiated byblue LED lamps under an atmosphere of Ar for 24 h. After the reactionwas complete the mixture was poured into a separator y funnel containing15 mL of ethyl acetate and 10 mL of H₂O. The layers were separated andthe aqueous layer was extracted with ethyl acetate (3×15 mi.). Thecombined organic layers were dried and concentrated in vacuo. The crudewas purified by silica gel column chromatography to afford product 2a asthe sole diastereomer (46.9 mg, 90% yield).

Crystal Structure of 2h.

X-ray quality crystals for 2h were obtained by slow diffusion inbenzene/hexanes at r

Empirical formula C₁₅H₁₅N₄Br Formula weight 339.18 Temperature 99.95 KCrystal system monoclinic Space group P2₁ Unit cell dimensions a=8.7786(8) Å α=90° . b =8.2454(7) Å β=110.205(4)° . c =10.7228(9) Å γ=90° . Volume 728,39(11) Å³ Z 2 Density (calculated) 1.546 Mg/m³Absorption coefficient 2,831 mm⁻¹ F(000) 344 Crystal size 0.117 × 0.074× 0.048 mm³ 2Θ range for data collection 4,048 to 77.302°. Index ranges−15<=h<=15,−14<= k<=14, −18<=1<=18 Reflections collected 54501Independent reflections 8255 [R(int) =0.0360] Data/restraints/parameters8755/1/182 Goodness-of-fit on F2 1.037 Final R indices [I>2sigma(I)] R₁=0.0268, wR₂ =0.0635 R indices (all data) R₂ =0.0341. wR₂ =0.0662Largest cliff peak and hole 0.723 and -0.503 e.ALÅ⁻³

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It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention. Theinvention illustratively described herein suitably may be practiced inthe absence of any element or elements, limitation or limitations whichis not specifically disclosed herein. The terms and expressions whichhave been employed are used as terms of description and not oflimitation, and there is no intention in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the invention. Thus, itshould be understood that although the present invention has beenillustrated by specific embodiments and optional features, modificationand/or variation of the concepts herein disclosed may be resorted to bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of this invention.

Citations to a number of patent and non-patent references are madeherein. The cited references are incorporated by reference herein intheir entireties. In the event that there is an inconsistency between adefinition of a term in the specification as compared to a definition ofthe term in a cited reference, the term should be interpreted based onthe definition in the specification.

We claim:
 1. A compound having Formula I or a tautomer thereof:

wherein: X is hydrogen or alkyl; n is 0-6; R¹ is hydrogen, alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally wherein R¹is a single 5-membered or 6-membered ring or two or more fused5-membered or 6-membered rings, wherein the single ring or two or morefused rings are carbocyclic or heterocyclic rings containing one or moreheteroatoms selected from N, O, and S, and wherein the ring or two ormore fused rings are saturated or unsaturated at one or more bonds,optionally wherein the single ring or more fused rings are substitutedat one or more positions with a substituent selected from alkyl, alkoxy,halo, amino, and cyano; R² is hydrogen, alkyl, aryl,

wherein R⁷ is hydrogen, alkyl, or aryl; R³ is hydrogen, hydroxyl, oroxo; R⁴ is hydrogen or alkyl; and R⁵ is hydrogen or

R⁶ is hydrogen, hydroxyl, or oxo; and R⁷ is hydrogen or alkyl.
 2. Thecompound of claim 1 having a Formula I(a) or a tautomer thereof:


3. The compound of claim 1 having a Formula I(b) or a tautomer thereof:


4. The compound of claim 1 having a Formula Ic or a tautomer thereof:


5. The compound of claim 1 having a Formula Id or a tautomer thereof:


6. The compound of claim 1 having a Formula I(e) or a tautomer thereof:


7. The compound of claim 1, wherein n is 0-2, and R¹ is selected fromphenyl optionally substituted at one or more positions with alkyl,alkoxy, halo, or haloalkyl; naphthyl; indolyl; and thiazolyl.
 8. Thecompound of claim 1 having a Formula I(f) or a tautomer thereof:


9. The compound of claim 1 having a Formula I(g) or a tautomer thereof:


10. The compound of claim 1 having a Formula I(h) or a tautomer thereof:


11. The compound of claim 1 having a Formula I(i) or a tautomer thereof:


12. The compound of claim 1 having a Formula I(j) or a tautomer thereof:


13. The compound of claim 1 having a Formula I(k) or a tautomer thereof:


14. The compound of claim 1 having a Formula I(l) or a tautomer thereof:


15. The compound of claim 1 having a formula selected from:


16. A complex having a formula represented as L.M²⁺(OTf)₂, wherein M isa divalent metal, Tf is triflyl, and L has a formula:

wherein R⁸ and R⁹ together form a 3-membered, 4-membered, 5-membered, or6-membered carbocyclic ring; and R¹⁰ and R¹¹ are alkyl.
 17. The complexof claim 16, wherein L has a formula:


18. The complex of claim 16, wherein L has a formula:


19. The complex of claim 16, wherein L has a formula:


20. The complex of claim 16, wherein L has a formula:


21. A method for preparing the compound of claim 1, the methodcomprising reacting a mixture comprising: (a) a compound having aformula

wherein: X is hydrogen or alkyl; n is 0-6; R¹ is hydrogen, alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally wherein R¹is a single 5-membered or 6-membered ring or two or more fused5-membered or 6-membered rings, wherein the single ring or two or morefused rings are carbocyclic or heterocyclic rings containing one or moreheteroatoms selected from N, O, and S, and wherein the ring or two ormore fused rings are saturated or unsaturated at one or more bonds,optionally wherein the single ring or more fused rings are substitutedat one or more positions with a substituent selected from alkyl, alkoxy,halo, amino, and cyano; and R⁷ is hydrogen or alkyl; (b) a complexhaving a formula L.M²⁺(OTf)₂, wherein M is a divalent metal, Tf istriflyl, and L has a formula:

wherein R⁸ and R⁹ are independently selected from alkyl, phenyl, or R⁸and R⁹ together form a 3-membered, 4-membered, 5-membered, or 6-memberedcarbocylic ring; and R¹⁰ and R¹¹ are alkyl; optionally wherein thecomplex is the complex of any of claims 16-20; (c) an oxidant(optionally wherein the oxidant is(2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)); and optionally (d) asalt (optionally wherein the salt is a sodium salt such as a sodiumphosphate salt such as disodium phosphate).